@article {pmid40116675,
year = {2025},
author = {Monteiro-Junior, RS},
title = {Virtual reality-based interventions for individuals with dementia: A potential further treatment and new perspectives.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251328723},
doi = {10.1177/13872877251328723},
pmid = {40116675},
issn = {1875-8908},
abstract = {This commentary highlights issues regarding virtual reality (VR)-based interventions for individuals with Alzheimer's disease, emphasizing their potential to improve cognitive function and delay decline. The aim of this manuscript is to present current findings and critically synthesize the practical applications of VR interventions. A recent meta-analysis demonstrates promising results, with VR interventions enhancing memory, executive functions, and overall cognition. Despite the limited number of studies and small sample sizes, findings suggest that engaging VR environments can motivate patients, fostering adherence to treatment. This commentary underscores the need for further research to validate these results and establish standardized methodologies for the effective use of VR in dementia care. Several methodological aspects and new perspectives are highlighted herein.},
}

@article {pmid40116674,
year = {2025},
author = {Richter, N and Breidenbach, L and Schmieschek, MH and Heiss, WD and Fink, GR and Onur, OA},
title = {Alzheimer-typical temporo-parietal atrophy and hypoperfusion are associated with a more significant cholinergic impairment in amnestic neurodegenerative syndromes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251324080},
doi = {10.1177/13872877251324080},
pmid = {40116674},
issn = {1875-8908},
abstract = {BackgroundTo date, cholinomimetics remain central in the pharmacotherapy of Alzheimer's disease (AD) dementia. However, postmortem investigations indicate that the AD-typical progressive amnestic syndrome may also result from predominantly limbic non-AD neuropathology such as TDP-43 proteinopathy and argyrophilic grain disease. Experimental evidence links a beneficial response to cholinomimetics in early AD to reduced markers of cholinergic neurotransmission. However, the cholinergic impairment varies among patients with a clinical AD presentation, likely due to non-AD (co)-pathologies.ObjectiveThis study examines whether AD-typical atrophy and hypoperfusion can provide information about the cholinergic system in clinically diagnosed AD.MethodsThirty-two patients with amnestic mild cognitive impairment or mild dementia due to AD underwent positron emission tomography (PET) with the tracer N-methyl-4-piperidyl-acetate (MP4A) to estimate acetylcholinesterase (AChE) activity, neurological examinations, cerebral magnetic resonance imaging (MRI) and neuropsychological assessment. The 'cholinergic deficit' was computed as the deviation of AChE activity from cognitively normal controls across the cerebral cortex and correlated gray matter (GM) and perfusion of temporo-parietal cortices typically affected by AD and basal forebrain (BF) GM.ResultsTemporo-parietal perfusion and GM, as well as the inferior temporal to medial temporal ratio of perfusion correlated negatively with the 'cholinergic deficit'. A smaller Ch4p area of the BF was associated with a more significant 'cholinergic deficit', albeit to a lesser degree than cortical measures.ConclusionsIn clinically diagnosed AD, temporo-parietal GM and perfusion are more closely associated with the 'cholinergic deficit' than BF volumes, making them possible markers for cholinergic treatment response in amnestic neurodegeneration.},
}

@article {pmid40115072,
year = {2025},
author = {Li, J and Hu, X and Tao, X and Li, Y and Jiang, W and Zhao, M and Ma, Z and Chen, B and Sheng, S and Tong, J and Zhang, H and Shen, B and Gao, X},
title = {Deconstruct the link between gut microbiota and neurological diseases: application of Mendelian randomization analysis.},
journal = {Frontiers in cellular and infection microbiology},
volume = {15},
number = {},
pages = {1433131},
pmid = {40115072},
issn = {2235-2988},
mesh = {Humans ; *Mendelian Randomization Analysis ; *Gastrointestinal Microbiome/genetics ; *Nervous System Diseases/genetics/microbiology ; Brain-Gut Axis ; Genome-Wide Association Study ; },
abstract = {BACKGROUND: Recent research on the gut-brain axis has deepened our understanding of the correlation between gut bacteria and the neurological system. The inflammatory response triggered by gut microbiota may be associated with neurodegenerative diseases. Additionally, the impact of gut microbiota on emotional state, known as the "Gut-mood" relationship, could play a role in depression and anxiety disorders.

RESULTS: This review summarizes recent data on the role of gut-brain axis in the pathophysiology of neuropsychiatric and neurological disorders including epilepsy, schizophrenia, Alzheimer's disease, brain cancer, Parkinson's disease, bipolar disorder and stroke. Also, we conducted a Mendelian randomization study on seven neurological disorders (Epilepsy, schizophrenia, Alzheimer's disease, brain cancer, Parkinson's disease, bipolar disorder and stroke). MR-Egger and MR-PRESSO tests confirmed the robustness of analysis against horizontal pleiotropy.

CONCLUSIONS: By comparing the protective and risk factors for neurological disorders found in our research and other researches, we can furtherly determine valuable indicators for disease evolution tracking and potential treatment targets. Future research should explore extensive microbiome genome-wide association study datasets using metagenomics sequencing techniques to deepen our understanding of connections and causality between neurological disorders.},
}

Humans
*Mendelian Randomization Analysis
*Gastrointestinal Microbiome/genetics
*Nervous System Diseases/genetics/microbiology
Brain-Gut Axis
Genome-Wide Association Study

@article {pmid40114925,
year = {2025},
author = {Ullah, S and Park, TJ and Park, JS and Atiq, A and Ali, J and Kang, MH and Ali, W and Choe, K and Kim, MO},
title = {Ambroxol attenuates detrimental effect of LPS-induced glia-mediated neuroinflammation, oxidative stress, and cognitive dysfunction in mice brain.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1494114},
pmid = {40114925},
issn = {1664-3224},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Lipopolysaccharides ; *Ambroxol/pharmacology/therapeutic use ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Neuroglia/drug effects/metabolism ; *Brain/metabolism/drug effects/pathology ; Male ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Antioxidants/pharmacology ; Mice, Inbred C57BL ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are multifactorial. Among various factors, lipopolysaccharides (LPSs) from Gram-negative bacteria, such as E. coli, are considered potential causative agents. Despite significant advancements in the field, there is still no cure. In this study, we investigated the neuroprotective effects of ambroxol against LPS-induced neuroinflammation, oxidative stress, neurodegeneration, and the associated cognitive dysfunction. Intraperitoneal injection of LPS (250 µg/kg every alternative day for a total of seven doses over 14 days) triggered glial cell activation, neuroinflammation, oxidative stress, and neurodegeneration in the mouse brain. Ambroxol treatment (30 mg/kg/day for 14 days) significantly reduced neuroinflammation and oxidative stress compared to LPS-treated mice. Immunoblotting and immunofluorescence results showed that ambroxol reduced levels of Toll-like receptor 4 (TLR4) and oxidative stress kinase phospho-c-Jun N-terminal Kinase 1 (p-JNK). It also decreased astrocyte and microglia activation in the cortex and hippocampus of LPS+ Amb-treated mice, as indicated by the downregulation of GFAP and Iba-1. Furthermore, ambroxol-reversed LPS-induced neuroinflammation by inhibiting inflammatory mediators, such as IL-1β and TNF-α, through regulation of the transcription factor p-NFkB. Persistent neuroinflammation disrupted the natural antioxidant mechanisms, leading to oxidative stress. Ambroxol treatment upregulated antioxidant markers, including Nrf-2, HO-1, and SOD, which were downregulated in the LPS-treated group. Additionally, ambroxol-inhibited lipid peroxidation, maintaining malondialdehyde levels in the mouse brain. Ambroxol also improves synaptic integrity by upregulating synaptic biomarkers, including PSD-95 and SNAP-23. Overall, ambroxol demonstrated anti-inflammatory, antioxidant, and neuroprotective effects in LPS-treated mice, highlighting its potential benefits in neurological disorders.},
}

Animals
*Oxidative Stress/drug effects
*Lipopolysaccharides
*Ambroxol/pharmacology/therapeutic use
Mice
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
*Neuroinflammatory Diseases/drug therapy/metabolism
*Neuroglia/drug effects/metabolism
*Brain/metabolism/drug effects/pathology
Male
*Neuroprotective Agents/pharmacology/therapeutic use
Disease Models, Animal
Antioxidants/pharmacology
Mice, Inbred C57BL

@article {pmid40114707,
year = {2025},
author = {Kumari, A and Rahaman, A and Zeng, XA and Baloch, Z},
title = {Therapeutic potential and microRNA regulating properties of phytochemicals in Alzheimer's disease.},
journal = {Molecular therapy. Nucleic acids},
volume = {36},
number = {1},
pages = {102439},
pmid = {40114707},
issn = {2162-2531},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is characterized by the aggregation of Aβ (peptide) and neurofibrillary tangles along with inflammatory processes. Aging is a significant driver of these alterations, and dementia is a major cause of disability and mortality. Despite extensive clinical trials over the past two decades, no effective drug has been developed to improve AD symptoms or slow its progression, indicating the inefficiency of current treatment targets. In AD development, the molecular microenvironment plays a significant role. MicroRNAs (miRNAs) are a key component of this microenvironment, regulate post-transcriptional gene expression, and are expressed more abundantly in the brain than in other tissues. Several dysregulated miRNAs in AD have been linked to neuropathological changes, such as plaque and tangle accrual, as well as altered expression of notorious molecules. Preclinical studies have confirmed the efficacy of phytochemicals/food bioactive compounds (PCs/FBCs) in regulating miRNA expression, which makes them immensely beneficial for targeting miRNA-altered expression patterns in neuronal diseases. This review highlights the potential of miRNAs in driving AD pathology and its development. Furthermore, it discusses the therapeutic efficacy of PCs/FBCs and their miRNA-regulatory properties, especially focusing on antiinflammatory and antioxidant capacities for their development as effective AD agents.},
}

@article {pmid40114579,
year = {2025},
author = {Ahmad, F},
title = {Nano-healing: Exploring the Therapeutic Potentials of Nanomedicine for CNS Disorders.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128362577250227081919},
pmid = {40114579},
issn = {1873-4286},
abstract = {INTRODUCTION: Nanomedicine offers immense potential in the field of Central Nervous System (CNS) disorder treatment, encompassing conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and stroke.

METHOD: Through the utilization of nanotechnology-driven drug delivery systems, the efficacy of drugs can be amplified, their toxicity minimized, and their bioavailability increased, enabling them to effectively reach the intended site within the CNS. This review aims to examine the therapeutic possibilities that nanomedicine presents in addressing these debilitating disorders. This exploration entails an analysis of diverse nanotechnology- based approaches for CNS drug delivery, including polymeric nanoparticles, liposomes, dendrimers, and carbon nanotubes. Moreover, notable advancements in nanotechnology-based therapeutics for CNS disorders are highlighted, such as the application of nanoparticles for delivering curcumin in Alzheimer's disease, liposomes for delivering L-DOPA in Parkinson's disease, and dendrimers for delivering interferon-beta in multiple sclerosis.

RESULTS: Additionally, the potential of nanotechnology-based approaches in the treatment of epilepsy and stroke is discussed. The review concludes by addressing the challenges faced and emphasizes the significant potential of clinical trials in enhancing drug delivery and future prospects in the development of nanotechnology- based therapeutics for CNS disorders.

CONCLUSION: Overall, the therapeutic potential of nanomedicine in CNS disorder treatment is vast, instilling optimism for the creation of safe and effective therapies for these devastating conditions.},
}

@article {pmid40114255,
year = {2025},
author = {Pu, Y and Beck, D and Verspoor, K},
title = {Enriched knowledge representation in biological fields: a case study of literature-based discovery in Alzheimer's disease.},
journal = {Journal of biomedical semantics},
volume = {16},
number = {1},
pages = {3},
pmid = {40114255},
issn = {2041-1480},
support = {CI70200030//Australian Research Council/ ; },
mesh = {*Alzheimer Disease ; Humans ; Knowledge Discovery/methods ; },
abstract = {BACKGROUND: In Literature-based Discovery (LBD), Swanson's original ABC model brought together isolated public knowledge statements and assembled them to infer putative hypotheses via logical connections. Modern LBD studies that scale up this approach through automation typically rely on a simple entity-based knowledge graph with co-occurrences and/or semantic triples as basic building blocks. However, our analysis of a knowledge graph constructed for a recent LBD system reveals limitations arising from such pairwise representations, which further negatively impact knowledge inference. Using LBD as the context and motivation in this work, we explore limitations of using pairwise relationships only as knowledge representation in knowledge graphs, and we identify impacts of these limitations on knowledge inference. We argue that enhanced knowledge representation is beneficial for biological knowledge representation in general, as well as for both the quality and the specificity of hypotheses proposed with LBD.

RESULTS: Based on a systematic analysis of one co-occurrence-based LBD system focusing on Alzheimer's Disease, we identify 7 types of limitations arising from the exclusive use of pairwise relationships in a standard knowledge graph-including the need to capture more than two entities interacting together in a single event-and 3 types of negative impacts on knowledge inferred with the graph-Experimentally infeasible hypotheses, Literature-inconsistent hypotheses, and Oversimplified hypotheses explanations. We also present an indicative distribution of different types of relationships. Pairwise relationships are an essential component in representation frameworks for knowledge discovery. However, only 20% of discoveries are perfectly represented with pairwise relationships alone. 73% require a combination of pairwise relationships and nested relationships. The remaining 7% are represented with pairwise relationships, nested relationships, and hypergraphs.

CONCLUSION: We argue that the standard entity pair-based knowledge graph, while essential for representing basic binary relations, results in important limitations for comprehensive biological knowledge representation and impacts downstream tasks such as proposing meaningful discoveries in LBD. These limitations can be mitigated by integrating more semantically complex knowledge representation strategies, including capturing collective interactions and allowing for nested entities. The use of more sophisticated knowledge representation will benefit biological fields with more expressive knowledge graphs. Downstream tasks, such as LBD, can benefit from richer representations as well, allowing for generation of implicit knowledge discoveries and explanations for disease diagnosis, treatment, and mechanism that are more biologically meaningful.},
}

*Alzheimer Disease
Humans
Knowledge Discovery/methods

@article {pmid40112330,
year = {2025},
author = {Vasileva-Metodiev, SZ and Spargo, D and Klein, EG and Quevenco, FC and Cotton, S and Sanchez-Juan, P and Niimi, Y and Fowler, NR},
title = {Diagnostic journey and management of patients with mild cognitive impairment and Alzheimer's disease dementia: A multinational, real-world survey.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251322978},
doi = {10.1177/13872877251322978},
pmid = {40112330},
issn = {1875-8908},
abstract = {BackgroundAn Alzheimer's disease (AD) diagnosis made in the earliest symptomatic stages substantially benefits patients and their care partners. However, little is known regarding the clinical, healthcare system-level, and patient-specific barriers that hinder timely diagnosis and treatment.ObjectiveTo explore real-world practices surrounding the diagnostic journey and management of mild cognitive impairment (MCI)/AD dementia patients.MethodsData were drawn from Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of physicians treating MCI/AD dementia patients in France, Germany, Italy, Spain, the United Kingdom, the United States, and Japan between 2022 and 2024.ResultsOverall, 779 physicians reported data on 5551 patients. Physicians indicated current disease severity for 5421 patients; 37.2% had MCI (87.3% with suspected prodromal AD and 12.7% undetermined etiology), 17.2% AD with mild dementia, 31.1% AD with moderate dementia, and 14.5% AD with severe dementia. When not immediately diagnosed, the median time from first consultation to initial diagnosis was 8.9 and 12.6 weeks when patients first consulted and were diagnosed by either a primary care practitioner (PCP) or a specialist, respectively, compared with 21.6 weeks when a PCP referred to a specialist for diagnosis. Diagnostic delays were predominantly due to specialist wait times. Few patients had diagnostic AD biomarker tests (cerebrospinal fluid testing 9.5%, amyloid positron emission tomography 3.7%, AD-blood tests 5.3%).ConclusionsTimely MCI and AD diagnosis is impeded by referral delays and limited use of biomarker testing. Addressing these critical care gaps requires enhanced physician training, reduced wait times and increased biomarker utilization for early management.},
}

@article {pmid40112319,
year = {2025},
author = {Fuseya, K and Mimura, Y and Nakajima, S and Mimura, M and Kasanuki, K and Noda, Y},
title = {A systematic review and meta-analysis on the characteristics of transcranial magnetic stimulation treatment protocols for patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251325887},
doi = {10.1177/13872877251325887},
pmid = {40112319},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common neurodegenerative condition causing dementia. Currently, there has been no established non-pharmacological treatment for cognitive decline in patients with AD. Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) may be effective as a non-invasive treatment for improving cognitive function in AD.ObjectiveThis study aimed to examine the characteristics of rTMS treatment protocols for patients with ADMethodsWe conducted a systematic literature search on clinical trials on rTMS for improving cognitive decline in patients with AD, using the PubMed, PsycINFO, and Scopus databases and performed a meta-analysis according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. To clarify which cognitive domains in AD are improved by rTMS, meta-analyses were conducted on both global cognitive function and on each cognitive domain including verbal memory, processing speed, and executive function. In addition, sub-analyses of the treatment details of rTMS parameters including stimulation sites, stimulation frequency, stimulation intensity, and with/without the neuro-navigation technique and meta-regression analyses adjusting for gender, education, and the number of rTMS pulses were performed.ResultsThe results showed significant improvements in global cognitive function, while no significant findings in verbal memory, processing speed and executive function. No significant results were found in subgroup analysis or meta-regression.ConclusionsTo enrich the evidence for cognitive enhancement in AD with rTMS, the randomized controlled trials using a unified rTMS protocol with a larger sample size are warranted.},
}

@article {pmid40111937,
year = {2025},
author = {Wimo, A and Handels, R and Blennow, K and Kirsebom, KB and Selnes, P and Bon, J and Emersic, A and Gonzalez-Ortiz, F and Gregoric Kramberger, M and Sköldunger, A and Speh, A and Timón-Reina, S and Vromen, E and Jelle Visser, P and Winblad, B and Fladby, T},
title = {Cost-effectiveness of diagnosing and treating patients with early Alzheimer's disease with anti-amyloid treatment in a clinical setting.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251323231},
doi = {10.1177/13872877251323231},
pmid = {40111937},
issn = {1875-8908},
abstract = {BackgroundThe introduction of anti-amyloid treatments (AAT) for Alzheimer's disease (AD) has put the cost-effectiveness into focus.ObjectiveEstimate the potential cost-effectiveness of diagnostic pathways combined with AAT for early AD.MethodsDiagnostic accuracy of blood-based (BBM) and cerebrospinal fluid (CSF) biomarkers was obtained from Norwegian memory clinics using positron emission tomography (PET) as reference standard. In a health-economic model, the cost-effectiveness of three diagnostic strategies was estimated relying either on BBM (p-tau 217), CSF (Aβ42/40 ratio), and BBM with CSF confirmatory testing and compared with standard of care (SoC) and compared with CSF-AAT. The model consisted of a decision tree reflecting the diagnostic process and a subsequent Markov cohort model starting at mild cognitive impairment due to AD. All strategies except SoC were combined with AAT including costs of treatment (assumed €5000/year), infusions and monitoring.ResultsCompared with SoC all three strategies (CSF-AAT, BBM-AAT, and BBM-CSF-AAT) resulted in QALY gains at higher costs, with an incremental cost-effectiveness ratio (ICER) of 110k€, 141k€ and 110k€ respectively. Compared with CSF-AAT both BBM-AAT and BBM-CSF-AAT strategies resulted in QALYs lost at lower costs, with an ICER of 27k€ and 109k€ respectively. Results were particularly sensitive to the price of AAT and possible subcutaneous administration.ConclusionsCompared with SoC all three strategies are potentially not cost-effective as they exceeded the Swedish maximum willingness to pay threshold of €94,800 per QALY gained. BBM-CSF-AAT versus CSF-AAT is potentially cost-effective if willing to accept its QALY loss. Discussions on budget impact on different payers are needed after introducing AAT.},
}

@article {pmid40111934,
year = {2025},
author = {Gui, S and Zeng, F and Wu, Z and Nonaka, S and Sano, T and Ni, J and Nakanishi, H and Moriyama, M and Kanematsu, T},
title = {Lipopolysaccharides from Porphyromonas gingivalis indirectly induce neuronal GSK3β-dependent synaptic defects and cause cognitive decline in a low-amyloid-β-concentration environment in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326879},
doi = {10.1177/13872877251326879},
pmid = {40111934},
issn = {1875-8908},
abstract = {BackgroundLipopolysaccharides from Porphyromonas gingivalis (P.gLPS) are involved in the pathology of Alzheimer's disease (AD). However, the effect of P.gLPS on synaptic defects remains unclear.ObjectiveIn this study, we tested our hypothesis that P.gLPS induces synaptic defects in a low-amyloid-beta (Aβ)-concentration environment.MethodsMG6 microglia or N2a neurons was treated with P.gLPS (0.1 μg/mL), soluble Aβ42 (0.1 μM) or AL (combined P.gLPS and soluble Aβ42 at 0.1 μM).ResultsIn cultured MG6 microglia, increased the mRNA expression of TNF-α, IL-1β and IL-6 and the TNF-α release in parallel with increased NF-κB activation. In cultured N2a neurons, treatment with Aβ42, P.gLPS, and AL did not affect the mRNA expression of synapsin1 (SYN1) or post-synaptic density protein-95 (PSD-95). However, the treatment with conditioned medium from AL-exposed MG6 microglia (AL-MCM) significantly reduced the mRNA and protein expression of SYN1, PSD-95, and nuclear translocation of repressor element-1 silencing transcription factor (REST) but significantly increased the mRNA expression of TNF receptor type I (at 48 h) and glycogen synthase kinase (GSK)3β (at 24 h). TWS119 pretreatment (5 μM), a GSK3β specific inhibitor, significantly reversed the AL-MCM-induced reduction in the mRNA expression of SYN1 and PSD-95 and nuclear translocation of REST in cultured N2a neurons. In APP[NL-F/NL-F] mice, the immunofluorescence intensity of SYN1 and PSD-95 in cortical neurons was positively correlated with the index of the memory test but negatively correlated with that of TNF-α-positive microglia.ConclusionsThese observations demonstrate that P.gLPS induces neuronal GSK3β-dependent synaptic defects in a low-Aβ concentration environment via microglial activation.},
}

@article {pmid40111696,
year = {2025},
author = {Zeng, Y and Lin, D and Chen, A and Ning, Y and Li, X},
title = {Periodontal Treatment to Improve General Health and Manage Systemic Diseases.},
journal = {Advances in experimental medicine and biology},
volume = {1472},
number = {},
pages = {245-260},
pmid = {40111696},
issn = {0065-2598},
mesh = {Humans ; *Periodontitis/microbiology/therapy/immunology ; Dysbiosis/therapy/microbiology ; Microbiota ; Cardiovascular Diseases/therapy/microbiology/immunology ; },
abstract = {Periodontitis is increasingly recognized for its role in overall health and its associations with systemic conditions. Shared etiological factors, including microbiological, immunological, genetic, and environmental influences, have prompted interest in the potential impact of periodontal therapy on broader health outcomes. The oral microbiome plays a key role in the pathogenesis of periodontitis, with microbial imbalances (dysbiosis) contributing to inflammation and systemic disease progression. Additionally, immune responses to periodontal infection, such as chronic inflammation and dysregulated immune activity, are central to linking periodontitis with conditions like diabetes, cardiovascular disease, and autoimmune disorders. This chapter explores the connections between periodontal treatment and systemic diseases, such as diabetes, rheumatoid arthritis, cardiovascular disease, chronic kidney disease, Alzheimer's disease, digestive disorders, and respiratory disease. It also reviews the current research on the mechanisms, including microbial and immune factors, that underlie these associations. By emphasizing the role of periodontal health, the oral microbiome, and immune regulation in disease prevention and management, this chapter underscores the importance of integrated healthcare approaches to improve patient outcomes.},
}

Humans
*Periodontitis/microbiology/therapy/immunology
Dysbiosis/therapy/microbiology
Microbiota
Cardiovascular Diseases/therapy/microbiology/immunology

@article {pmid40111689,
year = {2025},
author = {Mattos, MCO and Vivacqua, A and Carneiro, VMA and Grisi, DC and Guimarães, MDCM},
title = {Interaction of the Systemic Inflammatory State, Inflammatory Mediators, and the Oral Microbiome.},
journal = {Advances in experimental medicine and biology},
volume = {1472},
number = {},
pages = {121-132},
pmid = {40111689},
issn = {0065-2598},
mesh = {Humans ; *Microbiota/immunology ; *Mouth/microbiology/immunology ; *Inflammation Mediators/metabolism ; *Inflammation/microbiology/immunology ; *Periodontitis/microbiology/immunology ; Dysbiosis/microbiology/immunology ; Animals ; },
abstract = {Humans are biological units that host numerous microbial symbionts and their genomes, which together form a superorganism or holobiont. Changes in the balance of the oral ecosystem can have consequences for both general and oral health, such as cavities, gingivitis, and periodontitis. Periodontitis is initiated by a synergistic and dysbiotic microbial community that causes local inflammation and destruction of the tooth's supporting tissues, potentially leading to systemic inflammation. This inflammation caused by periodontal disease has been associated with various systemic alterations, and the immune system is largely responsible for the body's exacerbated response, which can induce and exacerbate chronic conditions. Studies indicate that subgingival microorganisms found in periodontitis reach the bloodstream and are distributed throughout the body and, therefore, can be found in distant tissues and organs. Among all diseases associated with periodontal disease, diabetes mellitus presents the strongest and most elucidated link, and its bidirectional relationship has already been demonstrated. Chronic hyperglycemia favors the worsening of periodontal parameters, while the aggravation of periodontal parameters can promote an increase in glycemic indexes. Other systemic diseases have been related to periodontitis, such as Alzheimer's, chronic kidney disease, atherosclerosis, and respiratory diseases. The importance of periodontal control may suggest a reduction in the chances of developing chronic inflammatory diseases because these two alterations often share inflammatory pathways and, for this reason, may influence each other.},
}

Humans
*Microbiota/immunology
*Mouth/microbiology/immunology
*Inflammation Mediators/metabolism
*Inflammation/microbiology/immunology
*Periodontitis/microbiology/immunology
Dysbiosis/microbiology/immunology
Animals

@article {pmid40111567,
year = {2025},
author = {Bhratee, A and Chatterjee, D and Kaur, R and Singh, S},
title = {Protective mechanism of apigenin in proton pump inhibitor-associated progressive cognitive impairment in adult zebrafish via targeting GSK-3β pathway.},
journal = {Metabolic brain disease},
volume = {40},
number = {4},
pages = {155},
pmid = {40111567},
issn = {1573-7365},
mesh = {Animals ; *Zebrafish ; *Apigenin/pharmacology/therapeutic use ; *Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism/prevention & control ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Proton Pump Inhibitors/pharmacology ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Male ; },
abstract = {Cognitive impairment is characterized by memory loss and difficulty in focusing, remembering, adhering to directions, and solving problems; commonly seen in an elderly population. Apigenin (APG) (4', 5, 7-trihydroxyflavone) is a flavonoid with several positive health benefits, including chemoprevention, antioxidant and can suppress inflammatory responses by inhibiting TNF-α and IL-1β levels. In this experimental study, we observed the possible neuroprotective effects of APG in the zebrafish model exposed to Lansoprazole (LPZ), a proton pump inhibitor known to induce cognitive impairment through hyperactivation of GSK-3β pathway. This experiment involves 12 adult zebrafish per group, where one group received LPZ (100 mg) as a toxin for 7 days and APG (25, 50, and 100 mg/kg) as treatment, while DPZ (5 mg/kg) served as a standard comparison over the same period. Neurobehavioral tests such as T-Maze, Novel Tank Test (NTT), and Novel Object Recognition (NOR) were performed. Several biochemical assessments were also performed to evaluate the level of lipid peroxidation (LPO), glutathione (GSH), nitrite (NO), acetylcholinesterase activity (AChEs), catalase activity, neurotransmitters (GABA and glutamate), neuroinflammatory markers (IL-1β, TNF-α, and IL-10), and histopathological analysis. The results showed that apigenin enhanced memory function, improved neurotransmitter balance, decreased oxidative stress markers, regulated the production of proinflammatory cytokines, and inhibited GSK-3β activity. Additionally, the co-administration of a GSK-3β inhibitor further promoted neuroprotection and cognitive enhancement facilitated by apigenin, highlighting the importance of the GSK-3β signaling pathway. These findings highlight the potential of apigenin as a natural compound for mitigating cognitive dysfunction. However, this study should also include long-term toxicity assessments and deeper molecular analysis to elucidate Apigenin's mechanism of action fully. Future research should address these gaps to validate its therapeutic potential.},
}

Animals
*Zebrafish
*Apigenin/pharmacology/therapeutic use
*Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism/prevention & control
*Neuroprotective Agents/pharmacology/therapeutic use
*Proton Pump Inhibitors/pharmacology
Oxidative Stress/drug effects
Signal Transduction/drug effects
Male

@article {pmid39964126,
year = {2025},
author = {McIntyre, RS and Rasgon, N and Goldberg, J and Wong, S and Le, GH and Mansur, RB and Rosenblat, JD and Teopiz, KM and Stahl, SM},
title = {The effect of glucagon-like peptide-1 and glucose dependent insulinotropic polypeptide receptor agonists on neurogenesis, differentiation, and plasticity (Neuro-GDP): potential mechanistically informed therapeutics in the treatment and prevention of mental disorders.},
journal = {CNS spectrums},
volume = {30},
number = {1},
pages = {e23},
doi = {10.1017/S1092852925000124},
pmid = {39964126},
issn = {1092-8529},
mesh = {Humans ; *Mental Disorders/drug therapy ; *Neuronal Plasticity/drug effects ; *Receptors, Gastrointestinal Hormone/agonists ; *Neurogenesis/drug effects ; Animals ; *Glucagon-Like Peptide 1/agonists/metabolism ; Glucagon-Like Peptide-1 Receptor ; },
abstract = {Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (RAs) mimic naturally occurring GLP-1 and GIP and are highly effective anti-diabetic and anti-obesity agents. In addition to their robust acute and long-term effects on weight, metabolism, and blood pressure, these agents also reduce cardiovascular mortality as well as stroke risk and associated consequences. A replicated and convergent body of preclinical evidence also indicates that incretin receptor agonists activate molecular effectors critical to neuroplasticity, neuroprotection, and anti-apoptosis. Herein, we propose that GLP-1 RAs and GIP RAs are promising transdiagnostic mechanistically informed therapeutics in the treatment and prevention of multiple domains of psychopathology, including general cognitive, reward, and motivation systems and mental disorders. Major neurocognitive disorders (eg, Alzheimer's Disease, Parkinson's Disease), alcohol and substance use disorders, traumatic brain injury, and depressive disorders are near-term therapeutic targets. In addition, GLP-1 RAs and GIP RAs have robust effects on comorbidities that differentially affect persons with mental disorders (eg, cardiovascular, cerebrovascular, and metabolic disorders) and psychotropic drug-related weight gain.},
}

Humans
*Mental Disorders/drug therapy
*Neuronal Plasticity/drug effects
*Receptors, Gastrointestinal Hormone/agonists
*Neurogenesis/drug effects
Animals
*Glucagon-Like Peptide 1/agonists/metabolism
Glucagon-Like Peptide-1 Receptor

@article {pmid40110667,
year = {2025},
author = {Pini, L and Imbimbo, BP},
title = {Rethinking biological biomarkers to track treatment efficacy in Alzheimer's disease: Focus on brain connectivity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {3},
pages = {e70083},
doi = {10.1002/alz.70083},
pmid = {40110667},
issn = {1552-5279},
}

@article {pmid40110649,
year = {2025},
author = {Liu, S and Maruff, P and Saint-Jalmes, M and Bourgeat, P and Masters, CL and Goudey, B and , },
title = {Predicting amyloid beta accumulation in cognitively unimpaired older adults: Cognitive assessments provide no additional utility beyond demographic and genetic factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {3},
pages = {e70036},
doi = {10.1002/alz.70036},
pmid = {40110649},
issn = {1552-5279},
support = {IC170100030//Australian Research Council Training Centre in Cognitive Computing for Medical Technologies/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; Female ; Aged ; Male ; *Alzheimer Disease/genetics ; *Neuropsychological Tests/statistics & numerical data ; *Machine Learning ; Biomarkers ; Cognition/physiology ; Aged, 80 and over ; Cohort Studies ; Positron-Emission Tomography ; Neuroimaging ; Risk Factors ; },
abstract = {BACKGROUND: Integrating non-invasive measures to estimate abnormal amyloid beta accumulation (Aβ+) is key to developing a screening tool for preclinical Alzheimer's disease (AD). The predictive capability of standard neuropsychological tests in estimating Aβ+ has not been quantified.

METHODS: We constructed machine learning models using six cognitive measurements alongside demographic and genetic risk factors to predict Aβ status. Data were drawn from three cohorts: Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Australian Imaging, Biomarker & Lifestyle (AIBL) study. Internal validation was conducted within A4 with external validations in ADNI and AIBL to assess model generalizability.

RESULTS: The highest area under the curve (AUC) for predicting Aβ+ was observed with demographic, genetic, and cognitive variables in A4 (median AUC = 0.745), but this was not significantly different from models without cognitive variables. External validation showed no improvement in ADNI and a slight decrease in AIBL.

DISCUSSION: Standard neuropsychological tests do not significantly enhance Aβ+ prediction in cognitively unimpaired adults beyond demographic and genetic information.

HIGHLIGHTS: Standard neuropsychological tests do not significantly improve the prediction of amyloid beta positivity (Aβ+) in cognitively unimpaired older adults beyond demographic and genetic information alone. Across three well-characterized cohorts, machine learning models incorporating cognitive measures failed to significantly improve Aβ+ prediction, indicating the limited relationship between cognitive performance on these tests and the risk of pre-clinical Alzheimer's disease (AD). These findings challenge assumptions about cognitive symptoms preceding Aβ+ screening and emphasize the need for developing more sensitive cognitive tests for early AD detection.},
}

Humans
*Amyloid beta-Peptides/metabolism
Female
Aged
Male
*Alzheimer Disease/genetics
*Neuropsychological Tests/statistics & numerical data
*Machine Learning
Biomarkers
Cognition/physiology
Aged, 80 and over
Cohort Studies
Positron-Emission Tomography
Neuroimaging
Risk Factors

@article {pmid40110480,
year = {2025},
author = {Wu, J and Teng, Y and Xie, Y and Xing, S and Zhi, S},
title = {Comparing the efficacy of physical therapy interventions in Alzheimer's disease: a network meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1541287},
pmid = {40110480},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disorder that significantly impairs cognitive function and daily living abilities, representing a major public health challenge. Given the multifactorial nature of AD, effective therapeutic interventions targeting both cognitive and functional decline are critical. This study aimed to conduct a comprehensive comparison of the therapeutic effects of music therapy, acupuncture therapy, game therapy, cognitive training therapy, and exercise therapy on AD patients through a network meta-analysis. Randomized controlled trials (RCTs) published up until 2024 were systematically retrieved from multiple databases. Data were extracted, including the first author, publication year, country, total sample size, mean participant age, type and duration of intervention, and outcome measures such as the Mini-Mental State Examination, Activities of Daily Living, and Alzheimer's Disease Assessment Scale-Cognitive Subscale. Statistical analyses were performed using the RevMan 5.3 and Stata 17 software. The analysis included 52 RCTs with a total of 3,409 participants, offering a strong dataset. The results indicated that game therapy produced statistically significant improvements in mental state and daily living abilities, while acupuncture therapy yielded the most pronounced improvements in cognitive function among AD patients. Notably, the comparative efficacy of these interventions suggests that game therapy may offer short-term benefits, particularly for mental health and functional abilities, whereas acupuncture therapy demonstrated superior long-term cognitive enhancements. In conclusion, tailored physical and cognitive interventions such as game therapy and acupuncture therapy may hold significant potential in optimizing treatment outcomes for AD patients, with implications for both clinical practice and future research.},
}

@article {pmid40109740,
year = {2025},
author = {Schäker-Hübner, L and Toledano-Pinedo, M and Eimermacher, S and Krasniqi, V and Porro-Pérez, A and Tan, K and Horn, G and Stegen, P and Elsinghorst, PW and Wille, T and Pietsch, M and Gütschow, M and Marco-Contelles, J and Hansen, FK},
title = {Contilisant-Belinostat Hybrids: Polyfunctionalized Indole Derivatives as Multineurotarget Drugs for the Potential Treatment of Alzheimer's Disease.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {3},
pages = {831-840},
pmid = {40109740},
issn = {2575-9108},
abstract = {In this work, we designed, synthesized, and evaluated two types of multineurotargeting compounds using a pharmacophore merging strategy, aiming to develop potential treatments for Alzheimer's disease. We combined belinostat, an FDA-approved unselective histone deacetylase (HDAC) inhibitor, with the 5-substituted indole core of contilisant, known for its antioxidant and neuroprotective properties as well as its potent inhibitory activity against monoamine oxidases (MAOs), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Among these, compounds 8c (HDAC1, IC50 = 0.019 μM; HDAC6, IC50 = 0.040 μM; AChE, IC50 = 20.06 μM; BChE, IC50 = 17.10 μM; MAO-B, IC50 = 2.14 μM), and 9c (HDAC1, IC50 = 0.126 μM; HDAC6, IC50 = 0.020 μM; AChE, IC50 = 2.73 μM; BChE, IC50 = 4.03 μM; MAO-B, IC50 = 1.18 μM) emerged as the most promising candidates. These compounds warrant further investigation as potential treatments for Alzheimer's disease due to their unique inhibition profiles and favorable mode of inhibition.},
}

@article {pmid40109529,
year = {2025},
author = {Zhou, T and Zhang, R and Ohulchanskyy, TY and Qu, J},
title = {Monitoring photobiomodulation of amyloid-β aggregation in 3D cultured cells using label-free nonlinear optical imaging.},
journal = {Biomedical optics express},
volume = {16},
number = {3},
pages = {1143-1155},
pmid = {40109529},
issn = {2156-7085},
abstract = {The accumulation of beta-amyloid (Aβ) peptide aggregates, commonly known as plaques, is considered a key hallmark in the development of Alzheimer's disease (AD). Recently, low-level light therapy (LLLT), also referred to as photobiomodulation (PBM), has emerged as a promising treatment approach for AD. Previous studies have shown that PBM reduces Aβ load primarily by enhancing the clearance capabilities of glia cells. However, it remains unclear whether PBM can directly reduce the formation of Aβ plaques in neuronal cells independent of the glia cell effect. In this study, we employed three-dimensional (3D) cultured HEK 293 APPsw cells as an AD model to investigate the impact of PBM on Aβ aggregation. We demonstrated that label-free two-photon excited fluorescence (TPEF) imaging and second harmonic generation (SHG) imaging are effective tools for monitoring Aβ aggregation in 3D cell models. The TPEF imaging results and subsequent quantification revealed that PBM, particularly with low-level near-infrared light from an 808 nm laser (compared to 1064, 1210, and 1470 nm lasers), significantly reduced Aβ aggregation, specifically plaques formation, in the 3D cultured cells, with the effect found to be dose-dependent. Moreover, a comprehensive analysis of protein expression in the 3D cultured cells revealed that PBM induces overexpression of the LRP1 receptor, which mediates Aβ degradation and thus leads to the reduction of Aβ aggregation. This study highlights the use of label-free nonlinear optical imaging to monitor Aβ aggregation in AD progression and provides novel insights into the effects of PBM on Aβ plaque formation in AD models.},
}

@article {pmid40109054,
year = {2025},
author = {Tuan, PM and Vu, DC and Van, SV and Thuy, NT and Tham, VM and Ngan, N},
title = {Phytochemical composition, antioxidant and enzyme inhibitory effects of Stahlianthus thorelii Gagnep. rhizomes.},
journal = {Acta chimica Slovenica},
volume = {72},
number = {1},
pages = {63-70},
doi = {10.17344/acsi.2024.9043},
pmid = {40109054},
issn = {1580-3155},
mesh = {*Rhizome/chemistry ; *Antioxidants/pharmacology/chemistry/isolation & purification ; *Plant Extracts/pharmacology/chemistry ; *Enzyme Inhibitors/pharmacology/chemistry/isolation & purification ; alpha-Amylases/antagonists & inhibitors/metabolism ; Acetylcholinesterase/metabolism ; Phytochemicals/pharmacology/chemistry/isolation & purification ; Monophenol Monooxygenase/antagonists & inhibitors/metabolism ; Cholinesterase Inhibitors/pharmacology/chemistry ; alpha-Glucosidases/metabolism ; },
abstract = {Stahlianthus thorelii Gagnep. is used in traditional medicine to treat various diseases. In this study, ethyl acetate (EtOAc) extract of S. thorelii rhizomes was analyzed for its phychemicals, antioxidant activity and inhibition against enzymes (acetylcholinesterase, α-amylase, α-glucosidase, and tyrosinase). The EtOAc extract showed the presence of ferulic acid, catechin, epicatechin, epigallocatechin gallate, quercetin, and kaempferol, with average levels ranging from 169.29 to 2449.60 μg/g. Analysis of the volatile components of the extract revealed that β-patchoulene (23.1%), (E)-nerolidyl isobutyrate (11.9%), and aristolene (10.8%) were the major compounds. The antioxidant potential of the extract measured by DPPH (IC50 = 86.94 ± 2.87 μg/mL) and ABTS (IC50 = 743.60 ± 56.52 μg/mL) assays showed promising results. The inhibitory effects against acetylcholinesterase and α-amylase demonstrated potential with IC50 values of 246.43 ± 11.39 and 789.84 ± 8.27 µg/mL, respectively. The findings above suggest that the EtOAc extract of S. thorelii could contribute to supporting the treatment of certain diseases such as diabetes and Alzheimer's.},
}

*Rhizome/chemistry
*Antioxidants/pharmacology/chemistry/isolation & purification
*Plant Extracts/pharmacology/chemistry
*Enzyme Inhibitors/pharmacology/chemistry/isolation & purification
alpha-Amylases/antagonists & inhibitors/metabolism
Acetylcholinesterase/metabolism
Phytochemicals/pharmacology/chemistry/isolation & purification
Monophenol Monooxygenase/antagonists & inhibitors/metabolism
Cholinesterase Inhibitors/pharmacology/chemistry
alpha-Glucosidases/metabolism

@article {pmid40109019,
year = {2025},
author = {Wang, L and Sooram, B and Kumar, R and Schedin-Weiss, S and Tjernberg, LO and Winblad, B},
title = {Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {3},
pages = {e70048},
doi = {10.1002/alz.70048},
pmid = {40109019},
issn = {1552-5279},
support = {//Private Initiative "Innovative ways to fight Alzheimer´s disease Leif Lundblad Family and others"/ ; //Strategic Research Program in Neuroscience (StratNeuro) funding for postdoctoral researchers at Karolinska Institutet/ ; //Stiftelsen för Gamla Tjänarinnor/ ; //Gun och Bertil Stohnes Stiftelse/ ; //Åhlén-stiftelsen/ ; //Tore Nilsons Stiftelse för Medicinsk Forskning/ ; FO2024-0287-HK-66//Hjärnfonden/ ; 2024-03573//Vetenskapsrådet/ ; //Margaretha af Ugglas Foundation/ ; //Foundation for Geriatric Diseases at Karolinska Institutet/ ; //Karolinska Institutet Research Grants/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism ; *tau Proteins/metabolism ; *Proteolysis ; Autophagy/physiology ; Protein Processing, Post-Translational ; Animals ; Proteasome Endopeptidase Complex/metabolism ; Lysosomes/metabolism ; Ubiquitin/metabolism ; },
abstract = {In Alzheimer's disease (AD), tau undergoes abnormal post-translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy - targeted protein degradation - recently emerged as a modality in drug discovery where bifunctional molecules bring the target protein close to the degradation machinery to promote clearance. Since 2016, this strategy has been applied to tau pathologies and attracted broad interest in academia and the pharmaceutical industry. However, a systematic review of recent studies on tau degradation mechanisms is lacking. Here we review tau degradation mechanisms (the ubiquitin-proteasome system and the autophagy-lysosome pathway), their dysfunction in AD, and tau-targeted degraders, such as proteolysis-targeting chimeras and autophagy-targeting chimeras. We emphasize the need for a continuous exploration of tau degradation mechanisms and provide a future perspective for developing tau-targeted degraders, encouraging researchers to work on new treatment options for AD patients. HIGHLIGHTS: Post-translational modifications, aggregation, and mutations affect tau degradation. A vicious circle exists between impaired degradation pathways and tau pathologies. Ubiquitin plays an important role in complex degradation pathways. Tau-targeted degraders provide promising strategies for novel AD treatment.},
}

Humans
*Alzheimer Disease/metabolism
*tau Proteins/metabolism
*Proteolysis
Autophagy/physiology
Protein Processing, Post-Translational
Animals
Proteasome Endopeptidase Complex/metabolism
Lysosomes/metabolism
Ubiquitin/metabolism

@article {pmid40109001,
year = {2025},
author = {Bai, P and Mondal, P and Liu, Y and Gomm, A and Suen, C and Yang, L and Zhu, B and Sun, H and Ran, C and Shen, S and Tanzi, RE and Zhang, C and Wang, C},
title = {HDAC11 displays neuropathological alterations and offers as a novel drug target for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {3},
pages = {e14616},
doi = {10.1002/alz.14616},
pmid = {40109001},
issn = {1552-5279},
support = {1R01AG086433/GF/NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital/ ; 1P30AG062421-01//MADRC/ ; },
mesh = {*Alzheimer Disease/drug therapy/pathology ; Animals ; *Mice, Transgenic ; Mice ; Humans ; *Histone Deacetylases/metabolism/drug effects ; *Brain/drug effects/pathology/metabolism ; *Disease Models, Animal ; Male ; Histone Deacetylase Inhibitors/pharmacology ; Female ; Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by amyloid pathology and neuroinflammation, leading to cognitive decline. Targeting histone deacetylase-11 (HDAC11) offers a novel therapeutic strategy due to its role in immune regulation.

METHODS: We conducted neuropathological analyses on human AD post mortem brain tissues and 5xFAD transgenic mice. We developed PB94, a brain-permeable HDAC11-selective inhibitor, and assessed its effects using live-animal imaging and behavioral studies.

RESULTS: HDAC11 was significantly upregulated in AD brains, correlating with amyloid pathology and neuroinflammatory markers. PB94 treatment reduced amyloid burden and neuroinflammation, improving cognitive function in 5xFAD mice.

DISCUSSION: Our findings highlight HDAC11 as a promising drug target for AD. PB94's ability to reduce amyloid pathology and neuroinflammation suggests its potential as an effective therapeutic. This study supports further exploration of HDAC11 inhibition as a treatment strategy for AD.

HIGHLIGHTS: Histone deacetylase-11 (HDAC11) is significantly upregulated in Alzheimer's disease (AD) brains and colocalizes with amyloid pathology and neuroinflammatory markers. Novel brain-permeable HDAC11-selective inhibitor PB94 demonstrates promising therapeutic potential for AD treatment. PB94 treatment reduces amyloid burden and neuroinflammation in AD mouse models, confirmed by live imaging studies. HDAC11 inhibition enhances microglial phagocytosis of amyloid beta proteins and modulates inflammatory cytokine levels. PB94 treatment improves cognitive function in AD mouse models while showing favorable brain penetration and selectivity.},
}

*Alzheimer Disease/drug therapy/pathology
Animals
*Mice, Transgenic
Mice
Humans
*Histone Deacetylases/metabolism/drug effects
*Brain/drug effects/pathology/metabolism
*Disease Models, Animal
Male
Histone Deacetylase Inhibitors/pharmacology
Female
Aged
Aged, 80 and over

@article {pmid40108882,
year = {2025},
author = {Davidson, M and Stanciu, GD and Rabinowitz, J and Untu, I and Dobrin, RP and Tamba, BI},
title = {Exploring novel therapeutic strategies: Could psychedelic perspectives offer promising solutions for Alzheimer's disease comorbidities?.},
journal = {Dialogues in clinical neuroscience},
volume = {27},
number = {1},
pages = {1-12},
doi = {10.1080/19585969.2025.2480566},
pmid = {40108882},
issn = {1958-5969},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Comorbidity ; *Hallucinogens/therapeutic use ; },
abstract = {The increasing prevalence of dementia within an ageing global population, combined with prolonged life expectancy, accentuates Alzheimer's disease (AD) as a multifaceted healthcare challenge. This challenge is further compounded by the limited therapeutic options currently available. Addressing the intricacies of AD management, the mitigation of comorbidities has emerged as a pivotal facet of treatment. Comorbid conditions, such as neurobehavioral symptoms, play a role in shaping the clinical course, management, and outcomes of this pathology; highlighting the importance of comprehensive care approaches for affected individuals. Exploration of psychedelic compounds in psychiatric and palliative care settings has recently uncovered promising therapeutic potential, enhancing neuroplasticity, emotional processing and connection. These effects are particularly relevant in the context of AD, where psychedelic therapy offers hope not only for mitigating core symptoms but also for addressing the array of comorbidities associated with this condition. The integration of this comprehensive method offers a chance to significantly enhance the care provided to those navigating the intricate landscape of AD. Therefore, the current paper reviews the intricate link between more frequent additional health conditions that may coexist with dementia, particularly in the context of AD, and explores the therapeutic potential of psychedelic compounds in addressing these concurrent conditions.},
}

Humans
*Alzheimer Disease/drug therapy
*Comorbidity
*Hallucinogens/therapeutic use

@article {pmid40107930,
year = {2025},
author = {Hendrix, SB and Sano, M and Lyketsos, C and Rosenberg, PB and Porsteinsson, AP and Brown, BL and Hedges, D and Cummings, JL},
title = {Cohen-mansfield agitation inventory total score as a measure of agitation and aggression in Alzheimer's disease: A factor analysis.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100056},
doi = {10.1016/j.inpsyc.2025.100056},
pmid = {40107930},
issn = {1741-203X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is often associated with agitation and aggression, which may impair function, impede care, and be a major source of stress for caregivers. The Cohen-Mansfield Agitation Inventory (CMAI) is often used to assess agitation and aggression. In its original, nursing-home version, it is a 29-item, caregiver-informed, clinician-administered 7-point scale that assesses the frequency of various agitation or aggressive behaviors. However, the instruction manual advises against the use of the total score in favor of a domain-based analysis. This recommendation has been followed in both clinical trials and practice. Because the CMAI is comprehensive and easy to administer, we sought to determine the validity of its total score as a single construct for assessing agitation and aggression in patients with AD.

METHODS: We used a previously conducted factor analysis of the CMAI scores from two risperidone trials in patients with dementia (N = 648), and a follow-up analysis of the subset of patients with psychosis of AD (N = 479), to examine, using vector analysis and an effect-size-versus-signal-to-noise ratio analysis, whether the total CMAI score could confidently be used as a global measure of agitation and aggression in AD.

RESULTS: Our findings suggest that the CMAI items from the dataset analyzed load into 4 clusters, which cover about 50 % of the total data variance. Surprisingly, items with the lowest signal-to-noise ratio (hitting, performing repetitious mannerisms, aimless pacing or wandering) had the strongest response to treatment (and vice versa), and belonged to different factors. The further observation that many items were spread among the factors, instead of primarily measuring a single factor or domain, suggests that there is a continuum of symptoms, and separating them into domains requires separating very similar items that measure two or more domains.

CONCLUSIONS: These findings suggest that assessing agitation and aggression via CMAI domains instead of the total score is likely to miss important behavioral signals. Using total CMAI score in clinical trials and practice, along with the assessment of individual items, is warranted.},
}

@article {pmid40107763,
year = {2025},
author = {, and , },
title = {[Expert consensus on disease-modifying therapy for Alzheimer's disease].},
journal = {Zhonghua yi xue za zhi},
volume = {105},
number = {},
pages = {1-11},
doi = {10.3760/cma.j.cn112137-20250304-00512},
pmid = {40107763},
issn = {0376-2491},
support = {2021ZD0201801//Science and Technology Innovation 2030-Major Project on "Brain Science and Brain-Like Research"/ ; 2022YFC3602600//National Key Research and Development Program of China/ ; },
abstract = {Alzheimer's disease (AD) poses a significant challenge to China's aging population, and treatment is now comprehensively shifting toward disease-modifying therapy (DMT). By targeting core pathophysiological mechanisms, DMT seeks to alter the natural progression of AD. As an emerging therapeutic paradigm, there is an urgent need for expert consensus to standardize the clinical use of DMT drugs in AD. This consensus systematically reviews both clinical practice and research advancements related to DMT for AD, including its target populations, contraindications and high-risk groups, pre-treatment evaluation procedures, administration methods and durations, efficacy assessments, and adverse event monitoring. It presents 17 recommendations to guide the clinical application of DMT in AD.},
}

@article {pmid40107503,
year = {2025},
author = {Zhu, L and Liu, C and Wang, Y and Zhu, X and Wu, L and Chen, L and Zhou, J and Wang, F},
title = {METTL3/IGF2BP2/IκBα axis participates in neuroinflammation in Alzheimer's disease by regulating M1/M2 polarization of microglia.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {105964},
doi = {10.1016/j.neuint.2025.105964},
pmid = {40107503},
issn = {1872-9754},
abstract = {BACKGROUND: Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD.

METHOD: Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N[6]-methyladenosine (m[6]A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF.

RESULTS: Stimulation with Aβ1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m[6]A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα.

CONCLUSION: Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.},
}

@article {pmid40107427,
year = {2025},
author = {Oh, JM and Kim, SH and Pandey, BP and Shin, WH and Son, HJ and Kwon, YJ and Kim, H},
title = {A stilbenoid, rhapontigenin, isolated from the root of Rheum palmatum L. acts as a potent BACE1 inhibitor.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {106484},
doi = {10.1016/j.fitote.2025.106484},
pmid = {40107427},
issn = {1873-6971},
abstract = {Seven compounds, comprising three anthraquinones and four stilbenoids, were isolated from the roots of Rheum palmatum L. These compounds include chrysophanol (1), aloe-emodin (2), aloe-emodin 8-O-β-D-glucopyranoside (3), desoxyrhapontigenin (4), rhapontigenin (5), desoxyrhaponticin (6), and piceatannol 3'-O-β-D-glucopyranoside (7). Among these, compound 5 showed potent β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activity with an IC50 value of 0.256 ± 0.008 μM, making it the most effective inhibitor obtained from herbal extracts to date, followed by compounds 3 (1.164 ± 0.108 μM), 6 (1.213 ± 0.193 μM), 7 (1.270 ± 0.130 μM), and 4 (2.028 ± 0.108 μM). Furthermore, kinetic analysis revealed that compound 5 acted as a mixed type-I inhibitor with an inhibition constant Ki value of 0.28 ± 0.07 μM. Notably, compound 2 exhibited potent Aβ aggregation inhibition with an IC50 value of 3.56 ± 0.19 μM, whereas compound 5 showed low Aβ aggregation inhibition with an IC50 value of >40 μM. The docking simulations revealed that compound 5 had a high binding affinity and interacted with TYR132, predicting it as a key residue for inhibition via hydrophobic interaction, and with THR133 via hydrogen bonding, in the flap region of BACE1. These results suggest that stilbenoids generally exhibit higher BACE1 inhibitory activity than that of anthraquinones, and that compound 5 (rhapontigenin) could be a promising candidate for the treatment of Alzheimer's disease as a potent BACE1 inhibitor.},
}

@article {pmid40107366,
year = {2025},
author = {Qin, W and He, J and Zhou, Y},
title = {Potential Mechanism and Efficacy Evaluation of Transcranial Focused Ultrasound Therapy for Alzheimer's Disease.},
journal = {Journal of neuroscience methods},
volume = {},
number = {},
pages = {110428},
doi = {10.1016/j.jneumeth.2025.110428},
pmid = {40107366},
issn = {1872-678X},
abstract = {BACKGROUND: Transcranial focused ultrasound (TFU) is emerging as a promising non-invasive therapy capable of blood-brain barrier (BBB) opening. TFU potentially allows the transfer of therapeutic agents to targeted brain areas for patients affected with Alzheimer's disease (AD).

NEW METHOD: The efficacy and mechanism of TFU in modulating BBB permeability in key brain regions, including the hippocampus and frontal lobe, are investigated in this research. A total of 20 participants aged 60-85 years were involved with AD. The treatment protocol involved three TFU sessions, spaced three weeks apart. The research encompasses pre-assessment and post-assessment of treatment with follow-up ranging from 5 to 12 months.

RESULTS: Statistical analysis involved paired t-tests to compare pre- and post-treatment cognitive scores, and ANOVA to predict significant differences in amyloid reduction across different brain regions, with the high decrease observed in the hippocampus. Multivariate Analysis (MANOVA) to explore the combined effect of cognitive and amyloid data. Linear Regression Analysis to predict cognitive improvement from amyloid plaque reduction. Longitudinal analysis for time-to-event analysis assessing the durability of effects over time.

Florbetaben Positron Emission Tomography (PET) scans demonstrated a reduction in β-amyloid plaque burden, with a 15% average decrease in the treated brain regions. No adverse effects on disease progression were observed up to 1 year after treatment.

CONCLUSION: This analysis presents the largest cohort of AD patients treated with TFU, with the longest follow-up to date. The treatment demonstrated safety and feasibility, with reversible BBB opening in multiple brain regions.},
}

@article {pmid40107340,
year = {2025},
author = {Tozihi, M and Nourazarian, A and Yousefi, H and Dehghan, G},
title = {Methylglyoxal-Induced Neuronal Dysfunction: Linking Diabetes to Alzheimer's Disease through Cytoskeletal Disruption.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177526},
doi = {10.1016/j.ejphar.2025.177526},
pmid = {40107340},
issn = {1879-0712},
abstract = {This study investigates how methylglyoxal affects Alzheimer's disease, which is common in patients with diabetes mellitus. Using SH-SY5Y cells as a model of AD, we investigated the effects of MGO on cell viability, morphology, inflammation, and stress responses. Exposure to MGO induces cytotoxicity, inflammation and oxidative stress that contribute to AD in diabetic patients. We analyzed how MGO (150-900 μM) affects SH-SY5Y cells and its effects on cell survival, gene expression, cytoskeletal integrity, stress indicators, and Aβ42 accumulation (dose- and time-dependent). MGO dramatically affected cell viability depending on the dose and exposure time. Cell death occurred via intrinsic (BAX, CASP9) and extrinsic (FAS, FASLG) apoptotic pathways. Markers related to insulin signaling such as INSR, IRS1, IRS2, SLC2A4, etc. were downregulated, whereas markers of inflammation such as TNF-α, IL-6 and oxidative markers such as HMOX1, G6PD, etc. were upregulated with MGO (P < 0.001). Changes in MAP2 and TUBB3 expression were associated with cytoskeletal damage (P < 0.01). High levels of Aβ42 and low SOD activity confirmed that oxidative stress was induced. LPS treatment exacerbated these effects (P < 0.01). The results highlight the possible role of MGO in cognitive decline associated with diabetes and suggest the need for novel treatment against MGO-related neurotoxicity.},
}

@article {pmid40105503,
year = {2025},
author = {Chen, YH and Wang, ZB and Liu, XP and Mao, ZQ and , },
title = {Cerebrospinal fluid LMO4 as a synaptic biomarker linked to Alzheimer's disease pathology and cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326286},
doi = {10.1177/13872877251326286},
pmid = {40105503},
issn = {1875-8908},
abstract = {BackgroundLIM-domain-only 4 (LMO4) is involved in neurodevelopment and synaptic plasticity, but its role in the pathogenesis of Alzheimer's disease (AD) remains unclear.ObjectiveTo investigate the association between cerebrospinal fluid (CSF) LMO4 levels and core AD biomarkers, neurodegeneration, and cognitive decline.MethodsWe included 703 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Associations between CSF LMO4 and AD biomarkers (Aβ42, Ptau181, amyloid PET) and postmortem neuropathology were evaluated. We also explored cross-sectional and longitudinal associations between CSF LMO4 and neurodegeneration and cognitive function. Receiver operating characteristic (ROC) analysis assessed the diagnostic accuracy of CSF LMO4 in distinguishing Aβ-positive from Aβ-negative participants and amyloid PET-confirmed AD cases. Mediation analysis explored the potential mediating role of CSF LMO4 between Aβ pathology and tau pathology.ResultsLMO4 levels were decreased in participants with abnormal Aβ levels and cognitive impairment. Lower CSF LMO4 levels were associated with increased Aβ and tau pathology, brain atrophy, cognitive decline, and postmortem neuropathology. CSF LMO4 partially mediated the relationship between Aβ and tau pathology and demonstrated acceptable discriminative ability in distinguishing Aβ-positive from Aβ-negative participants and amyloid PET-confirmed AD from non-AD cases.ConclusionsCSF LMO4 plays a crucial role in the pathogenesis and progression of AD and may represent a potential therapeutic target for AD treatment.},
}

@article {pmid40105173,
year = {2025},
author = {Deng, H and Wang, Y and Dai, Y and Wang, Q and Lu, H and Wang, Q},
title = {Unraveling the genetic mysteries of sarcopenia: A bioinformatics approach.},
journal = {Technology and health care : official journal of the European Society for Engineering and Medicine},
volume = {33},
number = {2},
pages = {1140-1153},
doi = {10.1177/09287329241291323},
pmid = {40105173},
issn = {1878-7401},
mesh = {*Sarcopenia/genetics ; Humans ; *Computational Biology/methods ; *Protein Interaction Maps/genetics ; Gene Regulatory Networks ; Gene Expression Profiling ; Gene Ontology ; Biomarkers/metabolism ; },
abstract = {Background As life expectancy increases and the global population ages, the incidence of sarcopenia is also increasing, highlighting the need for better diagnosis and treatment methods.ObjectiveTo study the genetic expression of sarcopenia using bioinformatics methods.MethodsA Weighted Gene Coexpression Network Analysis (WGCNA) was conducted to construct coexpression networks, along with protein-protein interaction networks. Diagnostic biomarker potential was evaluated using receiver operating characteristic curves. An analysis of Single-Sample Gene Set Enrichment Analysis (ssGSEA) was performed in order to determine the amount of immune cell infiltration. We analyzed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) enrichment using the KEGG.ResultsWGCNA identified modules linked to bone metabolism, ssGSEA showed unique gene enrichment patterns, and 268 genes were found to be differentially expressed in sarcopenia. Fourteen co-expression modules related to bone metabolism were identified, with one showing a strong positive correlation. KEGG pathway analysis indicated downregulation of the renin-angiotensin system and Alzheimer's disease pathways. The differentially expressed genes were primarily involved in adipocyte differentiation.ConclusionThis study analyzes genetic changes and immune cell patterns in sarcopenia, providing insights into its causes and potential diagnostic markers for future research on treatments.},
}

*Sarcopenia/genetics
Humans
*Computational Biology/methods
*Protein Interaction Maps/genetics
Gene Regulatory Networks
Gene Expression Profiling
Gene Ontology
Biomarkers/metabolism

@article {pmid40104800,
year = {2025},
author = {Wang, SQ and Wang, X and Guo, L and Chen, XX and Huang, XJ and Zhang, S and Ye, WC and Zhang, XQ and Shi, L and Wang, Y and Hu, LJ},
title = {In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {3},
pages = {475-482},
pmid = {40104800},
issn = {1948-5875},
abstract = {Eukaryotic elongation factor 2 kinase (eEF2K), an atypical Ser/Thr-protein kinase that regulates neuronal protein synthesis homeostasis via an inhibitory phosphorylation of eEF2, has emerged as a promising therapeutic target for several diseases, including Alzheimer's disease (AD). In this study, we employed molecular docking with an in-house natural product library of 4270 compounds, containing 2177 novel compounds and 603 new structural frameworks, to identify eEF2K inhibitors. Following virtual screening, 25 natural products were selected for in-vitro evaluation of eEF2 phosphorylation inhibition as well as protein synthesis promotion. Our findings identified that compounds 17 and 23 potently suppress eEF2K activity, increase protein synthesis, and concurrently induce neuritogenesis. Molecular dynamics simulations suggest that 17 and 23 may stably bind to the eEF2K protein. Our findings highlighted 17 and 23 as new natural eEF2K inhibitors and promising candidates for promoting neural differentiation, providing potential therapeutic leads for the treatment of AD.},
}

@article {pmid40104794,
year = {2025},
author = {Feng, S and Liang, SH},
title = {Identification of Indazole- and Azaindazole-Substituted Cyclopentapyrroles as G2019S Leucine-Rich Repeat Kinase 2 Inhibitors for the Treatment of CNS Disorders.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {3},
pages = {368-370},
pmid = {40104794},
issn = {1948-5875},
abstract = {This patent describes a novel class of novel indazole/azaindazole-substituted cyclopentapyrroles, which selectively inhibit the Leucine-Rich Repeat Kinase 2 (LRRK2) with G2019S mutation. These LRRK2 inhibitors are proposed for treating Parkinson's diseases, Alzheimer's disease, and other central nervous system (CNS) disorders.},
}

@article {pmid40104524,
year = {2025},
author = {Sullivan, AC and Zuniga, G and Ramirez, P and Fernandez, R and Wang, CP and Li, J and Davila, L and Pelton, K and Gomez, S and Sohn, C and Gonzalez, E and Lopez-Cruzan, M and Gonzalez, DA and Parker, A and Zilli, E and de Erausquin, GA and Seshadri, S and Espinoza, S and Musi, N and Frost, B},
title = {A Phase IIa clinical trial to evaluate the effects of anti-retroviral therapy in Alzheimer's disease (ART-AD).},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {2},
pmid = {40104524},
issn = {3005-1940},
abstract = {Retrotransposons constitute over 40% of the human genome. Studies in Drosophila, mice, cultured cells, and human brain show that retrotransposons are activated in tauopathies, including Alzheimer's disease, and causally drive neurodegeneration. The reverse transcriptase inhibitor 3TC (lamivudine) reduces retrotransposon activation and suppresses tau neurotoxicity among model systems. This phase 2a open-label trial (Pilot Study to Investigate the Safety and Feasibility of Anti-Retroviral Therapy for Alzheimer's Disease, NCT04552795, registered 09/10/2020) followed 12 participants with early Alzheimer's disease (MMSE > 24, CDR = 0.5) over 24 weeks to assess safety, tolerability, and feasibility of daily 300 mg 3TC treatment. The sample was well-educated (12-20 years) and culturally diverse (25% from underrepresented groups). In addition to a favorable safety profile and stable cognitive measures, notable significant changes in fluid-based biomarkers include reduction of glial fibrillary acidic protein (GFAP) (P = 0.03) in CSF, suggestive of reduced neuroinflammation, and elevation of Aβ42/40 (P = 0.009) in plasma, suggestive of reduced plaque load in the brain. These results warrant further exploration in a larger, placebo-controlled trial.},
}

@article {pmid40102464,
year = {2025},
author = {Ur Rahman, J and Hanif, M and Ur Rehman, O and Haider, U and Mian Qaisar, S and Pławiak, P},
title = {Stages prediction of Alzheimer's disease with shallow 2D and 3D CNNs from intelligently selected neuroimaging data.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {9238},
pmid = {40102464},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Neuroimaging/methods ; *Magnetic Resonance Imaging/methods ; *Neural Networks, Computer ; *Deep Learning ; Aged ; Female ; Brain/diagnostic imaging/pathology ; Male ; Cognitive Dysfunction/diagnostic imaging ; Positron-Emission Tomography/methods ; },
abstract = {Detection of Alzheimer's Disease (AD) is critical for successful diagnosis and treatment, involving the common practice of screening for Mild Cognitive Impairment (MCI). However, the progressive nature of AD makes it challenging to identify its causal factors. Modern diagnostic workflows for AD use cognitive tests, neurological examinations, and biomarker-based methods, e.g., cerebrospinal fluid (CSF) analysis and positron emission tomography (PET) imaging. While these methods are effective, non-invasive imaging techniques like Magnetic Resonance Imaging (MRI) are gaining importance. Deep Learning (DL) approaches for evaluating alterations in brain structure have focused on combining MRI and Convolutional Neural Networks (CNNs) within the spatial architecture of DL. This combination has garnered significant research interest due to its remarkable effectiveness in automating feature extraction across various multilayer perceptron models. Despite this, MRI's noisy and multidimensional nature requires an intelligent preprocessing pipeline for effective disease prediction. Our study aims to detect different stages of AD from the multidimensional neuroimaging data obtained through MRI scans using 2D and 3D CNN architectures. The proposed preprocessing pipeline comprises skull stripping, spatial normalization, and smoothing. It is followed by a novel and efficient pixel count-based frame selection and cropping approach, which renders a notable dimension reduction. Furthermore, the learnable resizer method is applied to enhance the image quality while resizing the data. Finally, the proposed shallow 2D and 3D CNN architectures extract spatio-temporal attributes from the segmented MRI data. Furthermore, we merged both the CNNs for further comparative analysis. Notably, 2D CNN achieved a maximum accuracy of 93%, while 3D CNN reported the highest accuracy of 96.5%.},
}

*Alzheimer Disease/diagnostic imaging
Humans
*Neuroimaging/methods
*Magnetic Resonance Imaging/methods
*Neural Networks, Computer
*Deep Learning
Aged
Female
Brain/diagnostic imaging/pathology
Male
Cognitive Dysfunction/diagnostic imaging
Positron-Emission Tomography/methods

@article {pmid40102200,
year = {2025},
author = {Wang, M and Jin, B and Jo, J},
title = {Acute Restraint Stress Induces Long-Lasting Synaptic Enhancement by Inhibiting AMPK Activation in AD Model Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {3},
pages = {e70335},
doi = {10.1111/cns.70335},
pmid = {40102200},
issn = {1755-5949},
support = {23YR1600//the Korean government (MSIP)/ ; 24-BR-03-05//KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT/ ; 10.13039/501100003725//Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; 10.13039/100020206//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; LQ24H310001//Natural Science Foundation of Zhejiang Province/ ; },
mesh = {Animals ; *Disease Models, Animal ; *Long-Term Potentiation/drug effects/physiology ; *Restraint, Physical ; *Stress, Psychological/psychology/metabolism ; *Alzheimer Disease/metabolism ; *Mice, Transgenic ; Mice ; AMP-Activated Protein Kinases/metabolism ; Male ; Hippocampus/drug effects/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Humans ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by a gradual synaptic loss. The progression of AD severely affects late-phase long-term potentiation (L-LTP), which is essential for long-term memory consolidation.

AIM: We have previously demonstrated the beneficial effects of acute restraint stress (ARS) on hippocampal LTP in AD mouse models. This study aimed to verify the effects and potential mechanisms of ARS on the maintenance of hippocampal L-LTP in two AD mouse models.

MATERIALS AND METHODS: 5xFAD and Tg2576 mice underwent a 30-min body immobilization protocol to induce ARS, followed by electrophysiological recordings of L-LTP (> 3 h) in the CA1 region of thehippocampus.

RESULTS: The ARS-exposed group exhibited significantly enhanced L-LTP compared to the control group. Maintenance of L-LTP requires new protein synthesis and signaling via the mammalian target of rapamycin (mTOR) pathway. Our findings revealed that ARS increased hippocampal adenosine triphosphate (ATP) production and reduced AMPK activity. Inactivation of AMPK and subsequent activation of the mTOR pathway were strongly associated with the ARS-facilitated enhancement of L-LTP. Furthermore, our experiments using the mTOR inhibitor rapamycin demonstrated that it effectively prevented the enhancement of L-LTP following ARS, underscoring the pivotal role of mTOR in this process.

CONCLUSION: ARS may significantly modify AMPK activation and mTOR regulation in L-LTP, potentially triggering the mechanisms of long-term memory consolidation in AD mouse model mice. Identifying these underlying mechanisms could help promote the development of novel pharmaceutical agents for the treatment of AD.},
}

Animals
*Disease Models, Animal
*Long-Term Potentiation/drug effects/physiology
*Restraint, Physical
*Stress, Psychological/psychology/metabolism
*Alzheimer Disease/metabolism
*Mice, Transgenic
Mice
AMP-Activated Protein Kinases/metabolism
Male
Hippocampus/drug effects/metabolism
TOR Serine-Threonine Kinases/metabolism
Humans

@article {pmid40102146,
year = {2025},
author = {Aho, E and Religa, D and Ding, M and Winblad, B and Jönsson, L and Modig, K},
title = {Patient management pathways in dementia - Resource utilisation, diagnosis and drug treatment in the Stockholm region, Sweden.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100132},
doi = {10.1016/j.tjpad.2025.100132},
pmid = {40102146},
issn = {2426-0266},
abstract = {BACKGROUND: New diagnostic and therapeutic options for Alzheimer's disease are beginning to be introduced and expected igto become more widely available in the coming years. Improved understanding of current pathways in diagnosis and initial care of patients with dementia can help inform choices around how best to integrate new technologies in existing care structures.

OBJECTIVES: The aim of this study is to describe the care management pathways defined by the involvement of specialist and primary care for individuals with newly diagnosed dementia. It also seeks to characterise individuals in different management pathways based on resource use prior to diagnosis, the type of dementia diagnosis received, and the proportion who receive symptomatic anti-dementia drug treatment.

DESIGN: Observational cohort study SETTING: Stockholm region, Sweden.

PARTICIPANTS: All newly diagnosed dementia cases between 1st January 2018 to 30th June 2020 (n = 9,781). Dementia diagnoses in primary care were based on Regional Stockholm health care database and diagnoses in specialist care were based on the National Patient Register in Sweden.

MEASUREMENTS: Care management pathways were categorized into three groups: primary care only (diagnosed and followed up in primary care), specialist, no follow-up (diagnosed in specialist care but not followed up in specialist care), and specialist with follow-up (diagnosed and followed up in specialist care). These classifications were based on patients' care episodes from the date of diagnosis and the subsequent 18 months. age at diagnosis, resource utilisation one-year prior diagnosis and diagnosis given and symptomatic anti-dementia treatment 18 months after initial diagnosis.

RESULTS: A total of 9,781 newly diagnosed dementia cases were identified. In the 18 months following diagnosis, 63 % of patients were diagnosed either partly or fully in specialist care, while 37 % were diagnosed solely in primary care. Patients diagnosed and managed only in primary care were older, spent more days in hospital, and received more social care in the year preceding their diagnosis. Their total care costs were also the highest. Alzheimer's disease was the most common diagnosis (48 %), while 27 % had an unspecified dementia diagnosis, varying by care setting (61 % for patients managed in primary care only and 6 % for patients diagnosed and followed up in specialist care). Overall, 47 % of patients received symptomatic anti-dementia treatment, with the highest share for patients diagnosed and followed up in specialist care (73 %) and the lowest in primary care only (19 %). Diagnosis varied by age and care setting Alzheimer's was most common in settings involving specialist care, whereas unspecified dementia was more common in primary care only regardless of age.

CONCLUSION: The findings that patients managed exclusively in primary care were older, had higher pre-diagnosis resource utilisation, and were less likely to receive specific diagnoses or anti-dementia treatments highlight the crucial role of primary care in diagnosing and managing dementia among older individuals with complex needs. Further research is needed to explore primary care's role in diagnosis and treatment across diverse healthcare systems. Future research is needed to explore whether and how new diagnostic tools and treatment for AD could facilitate timely diagnosis and care for older individuals with dementia in primary care.},
}

@article {pmid40101857,
year = {2025},
author = {Wang, J and Pan, H and Tang, H and Zhang, J and Li, T and Liu, Y and Huang, Y and Fei, Z and Wang, Y},
title = {Shuangxia Decoction attenuates sleep disruption in 5×FAD mice through neuroinflammation inhibition: an integrative analysis of transcriptomic and molecular biology investigations.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {119642},
doi = {10.1016/j.jep.2025.119642},
pmid = {40101857},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory and learning deficits. Circadian rhythm disruption-induced sleep disruption is frequently observed in AD patients. The Shuangxia Decoction (SXD) comprising Pinellia ternata (Thunb.) Breit. (Banxia) and Prunella vulgaris L. (Xiakucao), has been effectively used to treate sleep disruption for thousands of years. However, the mechanisms by which SXD treated AD through circadian rhythm-related pathways remain unexplored.

AIMS OF THE STUDY: This research sought to determine the efficacy, mechanisms, and active compounds of SXD in AD treatment via an integrative approach.

MATERIALS AND METHODS: We conducted a chronic jet lag (CJL) protocol in wild-type (WT) mice and monitored their rest/activity to compare their rest/activity period among WT, CJL, and CJD+SXD groups. In addition, we evaluated the impact of SXD on the cognitive and Aβ burden of 5×FAD mice by behavioral tests and Thioflavin staining. The underlying pathway analysis of SXD was revealed through transcriptomic and biology experimental validation. The active compounds of SXD were further analyzed using the UPLC-MS, molecular docking, and cellular thermal shift assay (CESTA).

RESULTS: Our study demonstrated a rapid recovery of rest/activity period in CJL mice following SXD treatment. Additionally, SXD treatment alleviated Aβ plaque accumulation, subsequently preserving cognitive behavior and motor ability in 5×FAD mice. Moreover, SXD significantly enhanced neuronal synaptic plasticity dendritic plasticity in CA1 neurons of 5×FAD mice. Transcriptomic analysis showed upregulation of the neuroinflammation-related pathway in 5×FAD mice. Subsequent heatmap analysis indicated a suppression of inflammatory factor secretion (Cd68, Trem2, IL-6, IL-1β, Cxc3r1, Tnf, et al.) and an increase of anti-inflammatory factor secretion (IL4, Ccl19, Ccl21a et al.,) following SXD treatment in the 5×FAD mice. Meanwhile, SXD upregulated positive regulators involved in the circadian rhythm like Bmal1 and Clock, and downregulated negative regulators like Nr1d1. Moreover, microglia exhibited an amoeboid morphology characterized by few processes and rounded cell bodies in 5×FAD mice, whereas the age-matched SXD group maintained microglia with a ramified appearance. Additionally, our study identified 20 major components of SXD and identified 3-(3,4-Dihydroxyphenyl) lactic acid, Salviaflaside, and Ilexhainanoside D for further molecular docking with REV-ERBα (NR1D1), a commonly used circadian target. Salviaflaside further showed a strong bind with REV-ERBα via CESTA.

CONCLUSIONS: Our findings indicate that SXD may rescue circadian rhythm in 5×FAD mice through specifically binding to REV-ERBα in microglia to activate the BMAL1/ CLOCK pathway, thus inhibiting transcription of inflammatory factors, contributing to alleviating neuroinflammation and impeding AD progression. Our results offer a scientific foundation for developing SXD-based therapies in the early stage of AD, where sleep disruption precedes cognitive decline, offering potential leads for clinical trials to improve sleep quality thus delaying neurodegeneration in AD patients.},
}

@article {pmid40101674,
year = {2025},
author = {Iaccarino, L and Burnham, SC and Tunali, I and Wang, J and Navitsky, M and Arora, AK and Pontecorvo, MJ},
title = {A practical overview of the use of amyloid-PET Centiloid values in clinical trials and research.},
journal = {NeuroImage. Clinical},
volume = {46},
number = {},
pages = {103765},
doi = {10.1016/j.nicl.2025.103765},
pmid = {40101674},
issn = {2213-1582},
abstract = {The density of brain amyloid-beta neuritic plaque accumulation, a marker of Alzheimer's disease (AD), can be visualized and quantified using amyloid-positron emission tomography (PET). Amyloid-PET data can be obtained using different tracers and methodologies; therefore, comparison across studies can be difficult. The introduction of Centiloids in 2015 allowed for the transformation of amyloid-PET quantitative data to a common scale, enhancing comparability across studies and potentially enabling pooled analysis. Since then, Centiloid values have been used increasingly in research and clinical trials for multiple purposes, being tested and validated with a variety of clinical, biomarker and pathological standards of truth. In clinical trials, Centiloid values have been used for patient selection, to confirm the presence of AD pathology, as well as for treatment monitoring, especially in trials of disease-modifying treatments such as amyloid-targeting therapies. Building on their widespread adoption, Centiloid values are increasingly being integrated into commercially available software solutions for quantifying amyloid-PET, paving the way for real-world applications at the community level. This article addresses frequently asked questions about Centiloid definition, implementation, interpretation, and caveats, and also summarizes the available literature on published thresholds, ultimately supporting wider access and informed use of Centiloid values in Alzheimer's disease research.},
}

@article {pmid40101029,
year = {2025},
author = {Liu, D and Zhao, Y and Liu, R and Qiao, B and Lu, X and Bei, Y and Niu, Y and Yang, X},
title = {Traditional Chinese medicine as a viable option for managing vascular cognitive impairment: A ray of hope.},
journal = {Medicine},
volume = {104},
number = {11},
pages = {e41694},
doi = {10.1097/MD.0000000000041694},
pmid = {40101029},
issn = {1536-5964},
mesh = {Humans ; *Medicine, Chinese Traditional/methods ; *Dementia, Vascular/drug therapy ; *Cognitive Dysfunction/drug therapy/etiology ; *Drugs, Chinese Herbal/therapeutic use ; },
abstract = {Vascular cognitive impairment (VCI) is a prevalent cognitive disorder resulting from cerebrovascular disease and encompasses a spectrum of cognitive deficits, ranging from mild impairment to vascular dementia (VD). VCI is responsible for a minimum of 20% to 40% of all cases of dementia, with its prevalence ranking second only to Alzheimer's disease on a global scale. The pathogenesis of VCI is complex and includes a lack of cholinergic nerve cells, inflammation, oxidative stress, alterations in the blood-brain barrier, and cell apoptosis. Current guideline-recommended drugs have unsatisfactory therapeutic effects. However, traditional Chinese medicine (TCM) has long been associated with treating dementia, and numerous studies regarding treating dementia with TCM have been conducted. The etiology and pathogenesis of VaD are linked to deficiencies in the spleen and kidney, as well as phlegm turbidity. Treatment involves benefiting the spleen and kidney, improving blood circulation, removing blood stasis, and dispelling phlegm. Moreover, TCM presents benefits such as few adverse effects, low cost, long-term use suitability, and preventive effects. This review outlines the pathogenesis of VCI in both modern medicine and TCM, examines traditional prescriptions and single-agent ingredients with their pharmacological effects, emphasizes TCM's unique features, and explores its multi-targeted approach to treating VCI.},
}

Humans
*Medicine, Chinese Traditional/methods
*Dementia, Vascular/drug therapy
*Cognitive Dysfunction/drug therapy/etiology
*Drugs, Chinese Herbal/therapeutic use

@article {pmid40100917,
year = {2025},
author = {Thau-Habermann, N and Gschwendtberger, T and Bodemer, C and Petri, S},
title = {Parthenolide regulates microglial and astrocyte function in primary cultures from ALS mice and has neuroprotective effects on primary motor neurons.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0319866},
pmid = {40100917},
issn = {1932-6203},
mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Sesquiterpenes/pharmacology ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Mice ; *Astrocytes/drug effects/metabolism ; Cells, Cultured ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; },
abstract = {Over the last twenty years, the role of microgliosis and astrocytosis in the pathophysiology of neurodegenerative diseases has increasingly been recognized. Dysregulation of microglial and astrocyte properties and function has been described also in the fatal degenerative motor neuron disease amyotrophic lateral sclerosis (ALS). Microglia cells, the immune cells of the nervous system, can either have an immunonegative neurotoxic or immunopositive neuroprotective phenotype. The feverfew plant (Tanacetum parthenium) derived compound parthenolide has been found to be capable of interfering with microglial phenotype and properties. Positive treatment effects were shown in animal models of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Now we were able to show that PTL has a modulating effect on primary mouse microglia cells, both wild type and SOD1, causing them to adopt a more neuroprotective potential. Furthermore, we were able to show that PTL, through its positive effect on microglia, also has an indirect positive impact on motor neurons, although PTL itself has no direct effect on these primary motor neurons. The results of our study give reason to consider PTL as a drug candidate for ALS.},
}

Animals
*Microglia/drug effects/metabolism/pathology
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology
*Sesquiterpenes/pharmacology
*Motor Neurons/drug effects/metabolism/pathology
*Neuroprotective Agents/pharmacology
Mice
*Astrocytes/drug effects/metabolism
Cells, Cultured
Mice, Transgenic
Superoxide Dismutase/metabolism

@article {pmid40100148,
year = {2025},
author = {Kawaguchi, K and Maeda, M and Murata, F and Nakashima, Y and Fukuda, H},
title = {Association of low bone mineral density and dementia in older women: insights from the Longevity Improvement and Fair Evidence Study.},
journal = {Age and ageing},
volume = {54},
number = {3},
pages = {},
doi = {10.1093/ageing/afaf058},
pmid = {40100148},
issn = {1468-2834},
support = {JPMJFR205J//Japan Science and Technology Agency's FOREST Program/ ; },
mesh = {Humans ; Female ; Aged ; *Bone Density ; *Dementia/epidemiology/diagnosis ; Japan/epidemiology ; Aged, 80 and over ; Risk Factors ; Osteoporosis/epidemiology/diagnosis ; Risk Assessment ; Longevity ; Alzheimer Disease/epidemiology/diagnosis ; },
abstract = {BACKGROUND: Both osteoporosis and dementia have emerged as important public health challenges in Japan's aging population. This study aimed to investigate the impact of low bone mineral density (BMD) on the subsequent risk of dementia in older Japanese women aged ≥65 years, given the overlapping demographics of individuals affected by these two conditions.

METHODS: This cohort study was conducted using osteoporosis screening data and insurance claims data from a municipality. We identified 8618 women (median age: 73 years) who underwent osteoporosis screening between April 2019 and March 2021. Participants with a BMD <80% of the young adult mean were assigned to a low-BMD group (n = 2297), whereas those with a BMD ≥80% were assigned to a control group (n = 6321). The study outcomes were new-onset all-cause dementia and Alzheimer's disease (AD). To estimate the risk of low BMD on these outcomes, we constructed Cox proportional hazards models that adjusted for covariates (age, care needs, year of cohort entry, comorbidities and medications) using inverse probability of treatment weighting.

RESULTS: The low-BMD group had a significantly higher risk of developing both all-cause dementia (adjusted hazard ratio: 1.58, 95% confidence interval: 1.20-2.08) and AD (1.61, 1.11-2.36) than the control group over approximately 30 months of follow-up.

CONCLUSION: These findings suggest that low BMD is associated with medium-term onset of dementia. Osteoporosis screenings could be useful not only for the secondary prevention of osteoporosis, but also for the primary prevention of dementia.},
}

Humans
Female
Aged
*Bone Density
*Dementia/epidemiology/diagnosis
Japan/epidemiology
Aged, 80 and over
Risk Factors
Osteoporosis/epidemiology/diagnosis
Risk Assessment
Longevity
Alzheimer Disease/epidemiology/diagnosis

@article {pmid40099247,
year = {2025},
author = {Mujib, MD and Rao, AZ and Haque, MFU and Alokaily, AO and Hussain, SS and Aldohbayb, AA and Qazi, SA and Hasan, MA},
title = {Modulated theta band frequency with binaural beat stimulation correlates with improved cognitive scores in Alzheimer's patients.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1543282},
pmid = {40099247},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) affects 50 million individuals worldwide, a number projected to triple by 2050. Due to discomfort through electrical and magnetic neuromodulation technologies, this is the first study to propose the potential of auditory binaural beat (BB) stimulation at an alpha frequency (10 Hz) for enhancing cognitive and neurological outcomes in AD patients.

METHODS: Twenty-five patients were divided into the experimental-Group (n = 15) and control-Group (n = 10). Psychometric and neurological assessments were conducted Pre-Treatment (Day 1) and Post-Treatment (Day 14) following consecutive days of binaural beats (BB) or auditory tone stimulation administered from Day 2 to Day 13.

RESULTS: A two-way ANOVA revealed a significant main effect of group (F = 6.087, p = 0.016) and session (F = 3.859, p = 0.024) on MMSE scores, with the experimental group showing significant improvement in MMSE scores (t = 7.33, p = 0.00000012) compared to the control group (p = 0.2306). Paired t-tests revealed a significant reduction in depression scores (DASS-21, t = 1.701, p = 0.0253) in the experimental group, while no significant improvements were noted in the control group. EEG recordings revealed significant changes in α-band, β-band, and γ-band power (p < 0.05). Moreover, The correlation between EEG bands and MMSE subparts showed that increased θ-band power in the experimental group was positively correlated (p < 0.05) with the frontal region during language tasks and in the frontal and central regions during registration and orientation tasks, indicating potential neurocognitive benefits.

DISCUSSION: The results of this research imply that BB stimulation has untapped potential as a non-invasive therapy for patients with AD, hence there is the need for further studies to manage the dementia epidemic.},
}

@article {pmid40098618,
year = {2025},
author = {Ye, CQ and Leng, J and Jin, MY and Meng, YD and Zhao, ZY and Meng, FX and Xu, X and Fan, SS and Luo, HB and Meng, XY},
title = {SysNatMed: rational natural medicine discovery by systems genetics.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1496061},
pmid = {40098618},
issn = {1663-9812},
abstract = {BACKGROUND: Although acknowledged as an important complement to modern medicine, the utility of natural medicine (NM) remains under-exploited. We aimed to develop a novel data-driven approach for natural medicine discovery.

METHODS: GWAS summary statistics of disease (Alzheimer's disease, i.e., AD, for the case study) and quantitative trait loci were collected from public sources. The ranking of disease-gene associations was established using summary-based Mendelian randomization. The comprehensive hierarchical relationships among ingredients, natural products, and target genes were compiled from the BATMAN-TCM v2.0 database. Based on the ranking of disease-gene associations and the comprehensive hierarchical relationships among ingredients, natural products, and target genes, we prioritized NM ingredients as potential candidates for AD management and examined the efficacy for AD prevention using rat AD models.

RESULTS: We developed a non-trivial transparent data-driven framework for systems genetics-based NM discovery. Among the 139 prioritized candidates for AD management, we demonstrated the efficacy of Dang Gui (Angelicae Sinensis Radix, ASR) and Dang Shen (Codonopsis Pilosula, CP) for AD prevention using rat models. Mechanistically, we showed that ASR may prevent AD-related damage through protection of neural cells, as well as inhibition of microglia, angiogenesis, inflammation, and extracellular matrices.

CONCLUSION: Our method holds potential for the development of new strategies of complementary medicine for disease treatment and prevention, especially for complex conditions involving a number of genes.},
}

@article {pmid40098612,
year = {2025},
author = {Zhang, W and Wang, R and Guo, R and Yi, Z and Wang, Y and Wang, H and Li, Y and Li, X and Song, J},
title = {The multiple biological activities of hyperoside: from molecular mechanisms to therapeutic perspectives in neoplastic and non-neoplastic diseases.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1538601},
pmid = {40098612},
issn = {1663-9812},
abstract = {In recent years, hyperoside (quercetin 3-O-β-D-galactopyranoside) has garnered significant attention due to its diverse biological effects, which include vasoprotective, antioxidant, anti-inflammatory, and anti-tumor properties. Notably, hyperoside has shown remarkable potential in cancer therapy by targeting multiple mechanisms; it induces apoptosis, inhibits proliferation, blocks angiogenesis, and reduces the metastatic potential of cancer cells. Furthermore, hyperoside enhances the sensitivity of cancer cells to chemotherapy by modulating key signaling pathways. Beyond neoplastic diseases, hyperoside also presents promising therapeutic applications in managing non-cancerous conditions such as diabetes, Alzheimer's disease, and pulmonary fibrosis. This review comprehensively examines the molecular mechanisms underlying hyperoside's anti-cancer effects and highlights its role in the treatment of cancers, including lung and colorectal cancers. Additionally, it explores the latest research on hyperoside's potential in addressing non-neoplastic conditions, such as pulmonary fibrosis, diabetes, and Parkinson's disease. By summarizing current findings, this review underscores the unique therapeutic value of hyperoside and its potential as a multifunctional treatment in both neoplastic and non-neoplastic contexts.},
}

@article {pmid40098057,
year = {2025},
author = {Franzmeier, N and Roemer-Cassiano, SN and Bernhardt, AM and Dehsarvi, A and Dewenter, A and Steward, A and Biel, D and Frontzkowski, L and Zhu, Z and Gnörich, J and Pescoller, J and Wagner, F and Hirsch, F and de Bruin, H and Ossenkoppele, R and Palleis, C and Strübing, F and Schöll, M and Levin, J and Brendel, M and Höglinger, GU},
title = {Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {31},
pmid = {40098057},
issn = {1750-1326},
support = {A2021026S//BrightFocus Foundation/ ; AARG-22-973496/ALZ/Alzheimer's Association/United States ; NA//Gerhard und Ilse Schick Stiftung/ ; },
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology ; Female ; Male ; *alpha-Synuclein/metabolism ; Aged ; *Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; Middle Aged ; Aged, 80 and over ; Biomarkers/metabolism/cerebrospinal fluid ; Cognitive Dysfunction/metabolism/pathology ; Amyloid/metabolism ; },
abstract = {BACKGROUND: Aggregated alpha-Synuclein (αSyn) is a hallmark pathology in Parkinson's disease but also one of the most common co-pathologies in Alzheimer's disease (AD). Preclinical studies suggest that αSyn can exacerbate tau aggregation, implying that αSyn co-pathology may specifically contribute to the Aβ-induced aggregation of tau that drives neurodegeneration and cognitive decline in AD. To investigate this, we combined a novel CSF-based seed-amplification assay (SAA) to determine αSyn positivity with amyloid- and tau-PET neuroimaging in a large cohort ranging from cognitively normal individuals to those with dementia, examining whether αSyn co-pathology accelerates Aβ-driven tau accumulation and cognitive decline.

METHODS: In 284 Aβ-positive and 308 Aβ-negative subjects, we employed amyloid-PET, Flortaucipir tau-PET, and a CSF-based αSyn seed-amplification assay (SAA) to detect in vivo αSyn aggregation. CSF p-tau181 measures were available for 384 subjects to assess earliest tau abnormalities. A subset of 155 Aβ-positive and 135 Aβ-negative subjects underwent longitudinal tau-PET over approximately 2.5 years. Using linear regression models, we analyzed whether αSyn SAA positivity was linked to stronger Aβ-related increases in baseline fluid and PET tau biomarkers, faster Aβ-driven tau-PET increase, and more rapid cognitive decline.

RESULTS: αSyn SAA positivity was more common in Aβ + vs. Aβ- subjects and increased with clinical severity (p < 0.001). Most importantly, αSyn positivity was also associated with greater amyloid-associated CSF p-tau181 increases (p = 0.005) and higher tau-PET levels in AD-typical brain regions (p = 0.006). Longitudinal analyses confirmed further that αSyn positivity was associated with faster amyloid-related tau accumulation (p = 0.029) and accelerated amyloid-related cognitive decline, potentially driven driven by stronger tau pathology.

CONCLUSIONS: Our findings suggest that αSyn co-pathology, detectable via CSF-based SAAs, is more prevalent in advanced AD and contributes to the development of aggregated tau pathology thereby driving faster cognitive decline. This highlights that a-Syn co-pathology may specifically accelerate amyloid-driven tau pathophysiology in AD, underscoring the need to consider αSyn in AD research and treatment strategies.},
}

Humans
*tau Proteins/metabolism
*Alzheimer Disease/metabolism/pathology
Female
Male
*alpha-Synuclein/metabolism
Aged
*Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
Middle Aged
Aged, 80 and over
Biomarkers/metabolism/cerebrospinal fluid
Cognitive Dysfunction/metabolism/pathology
Amyloid/metabolism

@article {pmid40097723,
year = {2025},
author = {Fantini, J and Azzaz, F and Aulas, A and Chahinian, H and Yahi, N},
title = {Preclinical assessment of a ganglioside-targeted therapy for Parkinson's disease with the first-in-class adaptive peptide AmyP53.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {9144},
pmid = {40097723},
issn = {2045-2322},
support = {Private funding//AmyPore/ ; },
mesh = {*alpha-Synuclein/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Gangliosides/metabolism ; Animals ; Humans ; Peptides/pharmacology/chemistry/therapeutic use ; Disease Models, Animal ; Mice ; Drug Evaluation, Preclinical ; },
abstract = {We propose a new concept for the treatment of Parkinson's disease (PD), which considers that its root cause, α-synuclein, is an intrinsically disordered protein (IDP) difficult to target by classic approaches. Upon binding to lipid raft gangliosides, α-synuclein shifts from random coil to α-helix, forming Ca[2+]-permeable oligomeric pores triggering a neurotoxicity cascade. We used the α-synuclein-ganglioside interaction as guideline to design a therapeutic peptide (AmyP53) that combines the respective flexible ganglioside-binding domains of α-synuclein and Alzheimer's β-amyloid protein. AmyP53 is an adaptive peptide, the first representant of a new therapeutic class. It acts as a competitive inhibitor of α-synuclein oligomer formation in brain cell membranes and prevents subsequent downstream synaptotoxicity, including the loss of dopaminergic neurons in an animal α-synuclein injection model of PD. It is active against both wild-type and mutant forms of α-synuclein. AmyP53 is administered intranasally without side effects. This new concept "target the target (gangliosides), not the arrow (IDP)" is distinct from classic α-synuclein centric approaches that did not cure PD so far.},
}

*alpha-Synuclein/metabolism
*Parkinson Disease/drug therapy/metabolism
*Gangliosides/metabolism
Animals
Humans
Peptides/pharmacology/chemistry/therapeutic use
Disease Models, Animal
Mice
Drug Evaluation, Preclinical

@article {pmid40097131,
year = {2025},
author = {Soni, U and Singh, K and Jain, D and Pujari, R},
title = {Exploring Alzheimer's Disease Treatment: Established Therapies and Novel Strategies for Future Care.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177520},
doi = {10.1016/j.ejphar.2025.177520},
pmid = {40097131},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function, memory impairment, and alterations in behavior. As the predominant etiology of dementia, AD affects millions of individuals worldwide, with its hallmark pathological feature being the accumulation of amyloid beta (Aβ) plaques, which disrupt neuronal function and progressively compromise brain structure. Early clinical manifestations often include forgetfulness, disorientation, and social withdrawal. Primarily impacting the elderly population, AD significantly impairs daily functioning and diminishes overall quality of life. Current therapeutic approaches for AD mainly focus on symptomatic relief and decelerating the disease's progression. Cholinesterase inhibitors, such as donepezil and rivastigmine, increase acetylcholine (ACh) levels to enhance cognitive function in individuals with mild to moderate AD. For individuals in more advanced stages of the disease, NMDA receptor antagonists modulate glutamate activity to mitigate excitotoxicity. In addition to pharmacological interventions, lifestyle modifications such as adherence to a balanced diet, regular physical activity, and cognitive engagement are advocated to support brain health. Novel therapeutic avenues are being explored to address underlying pathophysiological mechanisms, such as metal ion dysregulation within the brain. Furthermore, non-pharmacological approaches, including cognitive-behavioral therapy and patient support groups, provide essential behavioral and emotional support. Cutting-edge research continues to investigate innovative treatments, such as immunotherapies targeting amyloid plaques and tau tangles and neuroprotective compounds derived from natural sources. The goal of these multifaceted strategies is to alleviate symptoms, enhance quality of life, and offer hope for individuals and families affected by AD. This review provides a comprehensive summary of both established and emerging therapeutic interventions for the management of AD.},
}

@article {pmid40096973,
year = {2025},
author = {Alqudah, AS and Abaalkhail, NS and Alturki, AS and Naseer, YS and Almansour, SK},
title = {The prevalence of Alzheimer's disease among diabetic patients in Saudi Arabia.},
journal = {Saudi medical journal},
volume = {46},
number = {3},
pages = {244-253},
doi = {10.15537/smj.2025.46.3.20240778},
pmid = {40096973},
issn = {1658-3175},
mesh = {Humans ; Saudi Arabia/epidemiology ; Female ; *Alzheimer Disease/epidemiology ; Male ; Middle Aged ; Prevalence ; *Health Knowledge, Attitudes, Practice ; Surveys and Questionnaires ; Aged ; Adult ; Diabetes Mellitus/epidemiology ; Risk Factors ; },
abstract = {OBJECTIVES: To investigate the knowledge of Alzheimer's disease (AD) among 228 Saudi adults with diabetes, aiming to assess cognitive awareness through a questionnaire. It explores risk factors, symptoms, prevention strategies, and attitudes towards dementia, while integrating demographic data to illuminate cognitive landscapes and correlations between diabetes and cognitive health.

METHODS: Trained dietitians administered questionnaires to 228 adult Saudi diabetic participants, focusing on their understanding of AD across various domains. The study employed validated tools for data collection and amalgamated responses with demographic and medical details.

RESULTS: Of the 228 participants, 56.6% were female. Findings revealed a high acknowledgment of 3 subdomains of the Alzheimer's disease knowledge scale (ADKS) - risk factors, course, and diagnosis - with 75% agreement. However, lower acknowledgment rates with agreements were observed in the domains of life impact (71%), symptoms (71%), caregiving (72%), and treatment management (69%). Statistical analysis indicated significant differences in knowledge based on education levels (p≤0.05), with university-educated individuals demonstrating greater agreement across all ADKS subdomains.

CONCLUSION: The research highlights the need for enhanced awareness of AD among Saudi diabetic individuals. By integrating healthcare, education, and culturally sensitive interventions, the study advocates for targeted education to improve understanding of cognitive health and effective management strategies in this demographic, emphasizing the role of educational background in shaping perceptions.},
}

Humans
Saudi Arabia/epidemiology
Female
*Alzheimer Disease/epidemiology
Male
Middle Aged
Prevalence
*Health Knowledge, Attitudes, Practice
Surveys and Questionnaires
Aged
Adult
Diabetes Mellitus/epidemiology
Risk Factors

@article {pmid40096963,
year = {2025},
author = {Li, Y and Yang, C and Liu, X and Shu, J and Zhao, N and Sun, Z and Tabish, MS and Hong, Y and Liu, E and Wei, N and Sun, M},
title = {Potential therapeutic targets for Alzheimer's disease: Fibroblast growth factors and their regulation of ferroptosis, pyroptosis and autophagy.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.03.009},
pmid = {40096963},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a progressively worsening neurodegenerative disorder characterized primarily by the deposition of amyloid beta (Aβ) plaques in the brain and the abnormal aggregation of tau protein forming neurofibrillary tangles. These pathological changes lead to impaired neuronal function and cell death, subsequently affecting the structure and function of the brain. Fibroblast growth factors (FGFs) are a group of proteins that play crucial roles in various biological processes, including cell proliferation, differentiation, and survival. This article reviews the expression and regulation of FGFs in the central nervous system and how they affect neuronal survival, as well as the changes in FGF signaling pathways and its regulation of programmed cell death in AD. It particularly focuses on the impact of FGF1, FGF2, FGF21, other members of the FGF family, and FGFR on the pathophysiological mechanisms of AD. The potential of the PI3K/AKT/GSK-3β, Wnt/β-catenin, and NF-κB signaling pathways as targets for AD treatment is also discussed. Furthermore, the relationship between FGF-regulated ferroptosis, Pyroptosis and Autophagy and AD is explored, along with the role of these mechanisms in improving the progression of AD.},
}

@article {pmid40096940,
year = {2025},
author = {Abdel-Aal, RA and Meligy, FY and Maghraby, N and Sayed, N and Mohamed Ashry, IE},
title = {Comparing levetiracetam and zonisamide effects on rivastigmine anti-Alzheimer's activity in aluminum chloride-induced Alzheimer's-like disease in rats: Impact on α7 nicotinic acetylcholine receptors and amyloid β.},
journal = {Brain research},
volume = {},
number = {},
pages = {149573},
doi = {10.1016/j.brainres.2025.149573},
pmid = {40096940},
issn = {1872-6240},
abstract = {BACKGROUND AND AIM: Alzheimer's disease (AD) is the most progressive form of neurodegenerative disease, which severely impairs cognitive function. The leading class of drugs used to treat AD is acetylcholinesterase inhibitors (AChE-Is) as Rivastigmine (RIVA), partially ameliorate its cognitive symptoms. Since epilepsy is a common comorbidity with AD, we explored the potential that new the antiepileptic drugs; Levetiracetam (LEV) and Zonisamide (ZNS) may possess an additional therapeutic benefit to RIVA in AlCl3-induced AD rat model.

MATERIALS AND METHODS: AlCl3 was used to provoke AD in rats which were then supplemented with treatment drugs for 2 weeks. Treated groups were: Control, AlCl3, RIVA, LEV, RIVA + LEV, ZNS and RIVA + ZNS. Then, the behavioral tests; passive avoidance (PA), Morris water maze (MWM) and novel object recognition (NOR) were conducted to assess cognitive behavior and memory. The Hippocampal Aβ assembly was thoroughly examined by histopathology and ELISA. α7 Nicotinic ACh receptors' (α7nAChRs) expression was assessed immunohistochemically and by real-time quantitative polymerase chain reaction (qPCR). Caspase 3 expression was also assessed by real-time qPCR in hippocampal tissues.

RESULTS: AlCl3 administration impaired memory and cognitive functions in rats, augmented hippocampal Aβ deposition, with subsequent neurodegeneration and α7nAChRs down-regulation. LEV, but not ZNS, administration significantly mitigated AlCl3-induced cognitive impairment probably through suppression of amyloid β (Aβ) deposition, enhancement of neurogenesis and α7nAChRs expression. When combined to RIVA, ZNS treatment negatively affected cognition possibly through its impact on hippocampal Aβ and subsequent neuronal damage.

CONCLUSION: Although our results indicated that neither LEV nor ZNS provided any extra benefit to cognitive enhancements in AD rats receiving rivastigmine, LEV demonstrated positive effects individually while ZNS had negative effects when combined with RIVA. As a result, this study suggests the use of LEV rather than ZNS for managing epilepsy in patients with AD given that Alzheimer's and epilepsy can coexist.},
}

@article {pmid40096820,
year = {2025},
author = {Rust, R and Sagare, AP and Zhang, M and Zlokovic, BV and Kisler, K},
title = {The blood-brain barrier as a treatment target for neurodegenerative disorders.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2025.2480654},
pmid = {40096820},
issn = {1744-7593},
abstract = {INTRODUCTION: The blood-brain barrier (BBB) is a vascular endothelial membrane which restricts entry of toxins, cells and microorganisms into the brain. At the same time, the BBB supplies the brain with nutrients, key substrates for DNA and RNA synthesis, and regulatory molecules, and removes metabolic waste products from brain to blood. BBB breakdown and/or dysfunction have been shown in neurogenerative disorders including Alzheimer's disease (AD). Current data suggests that these BBB changes may initiate and/or contribute to neuronal, synaptic and cognitive dysfunction, and possibly other aspects of neurodegenerative processes.

AREAS COVERED: We first briefly review recent studies uncovering molecular composition of brain microvasculature and examine the BBB as a possible therapeutic target in neurodegenerative disorders with a focus on AD. Current strategies aimed at protecting and/or restoring altered BBB functions are considered. The relevance of BBB-directed approaches to improve neuronal and synaptic function, and to slow progression of neurodegenerative processes are also discussed. Lastly, we review recent advancements in drug delivery across the BBB.

EXPERT OPINION: BBB breakdown and/or dysfunction can significantly affect neuronal and synaptic function and neurodegenerative process. More attention should focus on therapeutics to preserve or restore BBB functions when considering treatments of neurodegenerative diseases and AD.},
}

@article {pmid40095667,
year = {2025},
author = {Lu, Y and Li, D and Yu, Y and Wang, Q and Li, A and Quan, Y and Xing, Y and , },
title = {Cerebrospinal fluid VGF is associated with the onset and progression of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251323002},
doi = {10.1177/13872877251323002},
pmid = {40095667},
issn = {1875-8908},
abstract = {BackgroundIt remains unclear whether cerebrospinal fluid (CSF) VGF (non-acronymic) is associated with the onset and progression of Alzheimer's disease (AD).ObjectiveTo assess the levels of CSF VGF throughout the AD continuum, and its association with primary AD pathology, cognition, brain atrophy, and brain metabolism.MethodsWe studied a total of 526 individuals including 377 amyloid-positive individuals (76 preclinical AD, 200 prodromal AD, and 101 AD dementia) and 149 amyloid-negative cognitively normal individuals. VGF peptide in CSF was analyzed using mass spectrometry.ResultsWe observed decreased CSF VGF in preclinical, prodromal, and AD dementia individuals than amyloid-negative cognitively normal individuals. Reduced CSF VGF was associated with cognitive decline, hippocampal atrophy, ventricle enlargement, and glucose hypometabolism at baseline, and it predicted a more marked deterioration over time.ConclusionsOur findings support the important contributions of VGF to disease pathogenesis and progression in the early stages of AD. Exploring the biologics modulating VGF might be a promising approach for AD prevention and early treatment.},
}

@article {pmid40095493,
year = {2025},
author = {Bhardwaj, S and Jindal, A and Singh, S and Kaur, R and Kaur Grewal, A},
title = {Pharmacological Evaluation of Aescin for Neuroprotection in Intracerebroventricular Streptozotocin Model of Alzheimer's Disease in Experimental Rats.},
journal = {Assay and drug development technologies},
volume = {},
number = {},
pages = {},
doi = {10.1089/adt.2024.130},
pmid = {40095493},
issn = {1557-8127},
abstract = {Alzheimer's disease (AD) is a neurological disorder that results in the loss of memory and cognitive functions linked to redox disbalance, neuroinflammation, neurotransmitters changes, and the accumulation of amyloid-beta (1-42) plaques in AD. In this study, rats were administered with intracerebroventricular (ICV) streptozotocin (STZ) to produce AD-like symptoms in rats. ICV-STZ bilaterally, 3 mg/kg, was infused on days 1 and 3 with the help of Hamilton syringe by fixing cannula at the target position of rat brain using coordinates -2 mm (anteriposterior), 1.6 mm Mediolateral (ML), and 1.5 mm (dorsoventral). Learning and spatial memory were checked using Morris water maze and elevated plus maze apparatus. In ICV-STZ, rats lost their spatial and learning memory, increased level of prooxidant like Lipid peroxidation (LPO), nitrite and reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) level. The increased level acetylcholinesterase (AChE) catalyzed acetylcholine (ACh) concentration indicates cholinergic neuron degeneration. Furthermore, we found raised inflammatory markers and altered neurotransmitters level after ICV-STZ. Administration of aescin (10, 20, and 30 mg/kg, p.o.) dose-dependently ameliorated the behavioral alteration and inhibited inflammatory markers like tumor necrosis factor-alpha, interleukin-6 (IL-6), and IL-1β. Furthermore, aescin restored antioxidants like GSH, SOD, and catalase and reduced the nitrite and lipid peroxidation level. AChE enzyme causes degradation of ACh, and its level was declined after treatment with aescin. Aescin also restored GABA, norepinephrine, and serotonin level in the brain with prevention of raised glutamate level. Moreover, the histopathological study confirmed neuronal pathogenesis, and aescin significantly achieved neuroprotective effect via preventing neuroinflammation, balancing redox potential, and inhibiting AChE enzyme.},
}

@article {pmid40095481,
year = {2025},
author = {Becker, C and Herschung, L and Gomm, W and Haenisch, B},
title = {Dementia diagnosis and prescription of antidementia drugs: An analysis of German claims data (2006-2016).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251319468},
doi = {10.1177/13872877251319468},
pmid = {40095481},
issn = {1875-8908},
abstract = {BackgroundUse of claims data allows to analyze health service characteristics of dementia, which is one of the most frequent cognitive disorders in Germany and worldwide.ObjectiveThe study aimed at describing the variability in dementia diagnoses and in antidementia drug prescription pattern.MethodsWe analyzed data from a population-based sample of one of the largest German statutory health insurances. The cohort included 30,403 patients with incident dementia diagnosis from 2006-2016. We described frequencies, patterns, and interrelations of diagnoses (Alzheimer's disease (AD), vascular dementia, other specific dementia, unspecified dementia (UD), antidementia drugs (ADD), and professional groups. We described switches in diagnostic and medication patterns between index quarter and following quarters, and evaluated the prescriptions in relation to national guidelines.ResultsA total of 87% of patients received a diagnosis of UD in at least one quarter of insurance. In the quarter of incident diagnosis, 14% of patients received more than one diagnostic code of dementia, whereas over the course of observation, the majority of patients received more than one diagnostic code (61%). Most patients were diagnosed by a general practitioner without involving a specialist. All professional groups primarily made UD diagnoses except specialists who mainly diagnosed AD. Thirty-five percent of all patients and 67% of AD patients were prescribed an ADD at least once.ConclusionsSpecialists made the most specific diagnoses and prescribed most ADDs. A specialist consultation may be advisable, but only 34% of patients visited one. Many AD patients might be left untreated due to underdiagnosis or -treatment.},
}

@article {pmid40095345,
year = {2025},
author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A},
title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40095345},
issn = {1559-1182},
abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.},
}

@article {pmid40095208,
year = {2025},
author = {Bhuiyan, P and Zhang, W and Liang, G and Jiang, B and Vera, R and Chae, R and Kim, K and Louis, LS and Wang, Y and Liu, J and Chuang, DM and Wei, H},
title = {Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the Brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {20},
number = {1},
pages = {26},
pmid = {40095208},
issn = {1557-1904},
support = {R01AG061447/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Administration, Intranasal ; Mice ; *Brain/drug effects/metabolism ; *Lithium Chloride/administration & dosage/toxicity ; *Depression/drug therapy ; *Alzheimer Disease/drug therapy/metabolism ; *Mice, Transgenic ; *Pyroptosis/drug effects/physiology ; Memory Disorders/drug therapy ; Male ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disease (AD) and has no treatment that can cure or halt the disease progression. This study explored the therapeutic potential of lithium salt dissolved in Ryanodex formulation vehicle (RFV) and delivered to the brain by intranasal application. We first compared lithium concentrations in the brain and blood of wild-type mice following intranasal or oral administration of lithium chloride (LiCl) dissolved in either RFV or water. The beneficial and side effects of intranasal versus oral LiCl in RFV in these mice were assessed and potential mechanisms underlying the efficacy of anti-inflammation and anti-pyroptosis in the brains were also investigated in both wild-type and 5XFAD Alzheimer's Disease (AD) mice brains.

METHODS: For the study of brain versus blood lithium concentrations, wild-type (WT) B6SJLF1/J mice at 2 months of age were treated with intranasal or oral LiCl (3 mmol/kg) dissolved in RFV or in water. Brain and blood lithium concentrations were measured at various times after drugs administration. Brain/blood lithium concentration ratios were then determined. For studying therapeutic efficacy versus side effects and their underlying mechanisms, 5XFAD and WT B6SJLF1/J mice were treated with intranasal LiCl (3 mmol/kg) daily, Monday to Friday each week, in RFV beginning at 2 or 9 months of age with a 12-week treatment duration. Animal behaviors were assessed for depression (tail suspension), cognition (fear conditioning and Y maze), olfaction (buried food test), and motor functions (rotarod) at the age of 5 and 12 months. Blood and brain tissue were harvested from these mice at 13 months. Blood biomarkers for the functions of thyroid (thyroid stimulating hormone, TSH) and kidney (creatinine) were measured using ELISA. Changes in protein expression levels of the endoplasmic reticulum Ca[2+] release channels type 1 InsP3 receptors (InsP3R-1), malondialdehyde (MDA)-modified proteins and 4-hydroxy-2-nonenal (4-HNE), pyroptosis regulatory proteins (NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, N-terminal of Gasdermin D (GSDMD)), cytotoxic (IL-1β, IL-18, IL-6, TNF-α) and cytoprotective (IL-10) cytokines and synapse proteins (PSD-95, synapsin-1) were determined using immunoblotting. Mouse body weights were monitored regularly.

RESULTS: Compared to oral LiCl in RFV nanoparticles, intranasal treatment of WT mice with LiCl in RFV markedly decreased blood concentrations at the time range of 30-120 min. The ratio of brain/blood lithium concentration after intranasal lithium chloride in RFV significantly increased, in comparison to those after oral administration lithium chloride in RFV or intranasal administration of lithium chloride in water. Intranasal lithium chloride in RFV inhibited both memory loss and depressive behavior in adult and aged 5XFAD mice. Additionally intranasal treatment of aged 5XFAD mice with LiCl in RFV effectively suppressed the increases in InsP3R-1, intracellular oxidative stress markers (4-HNE-bound and MDA-modified proteins), pyroptosis activation proteins (NLRP3, cleaved caspase-1, N-terminal GSDMD) and cytotoxic cytokines (IL-1β, IL-6, TNF-α), but reversed the down-regulation of cytoprotective cytokine IL-10. Intranasal LiCl in RFV also alleviated the loss of the postsynaptic synapse proteins PSD-95, but not synapsin-1, in aged 5XFAD mice. Blood level of the kidney function marker creatinine was significantly increased in 5XFAD than in WT mice in an age-dependent manner and this elevation was abolished by intranasal delivery of LiCl in RFV. Intranasal LiCl in RFV for 12 weeks in both WT or 5XFAD mice did not affect blood biomarkers for thyroid function, nor did it affect smell or muscle function or body weight.

CONCLUSION: Intranasal administration of LiCl in RFV significantly decreased lithium blood concentrations and increased brain/blood lithium concentration ratio, in comparison to its oral administration. Intranasal administration of LiCl in RFV robustly protected against both memory loss and depressive-like behavior, while had no side effects concerning thyroid and kidney toxicity in 5XFAD mice. These lithium-induced beneficial effects were strongly associated with lithium's suppression of InsP3R-1 Ca[2+] channel receptor increase, pathological neuroinflammation and activation of the pyroptosis pathway, as well as the loss of the synaptic protein PSD-95. Intranasal delivery of lithium salt in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and serve as a new treatment for both AD-associated dementia and depression with minimal unwanted side effects including peripheral organ toxicity.},
}

Animals
*Administration, Intranasal
Mice
*Brain/drug effects/metabolism
*Lithium Chloride/administration & dosage/toxicity
*Depression/drug therapy
*Alzheimer Disease/drug therapy/metabolism
*Mice, Transgenic
*Pyroptosis/drug effects/physiology
Memory Disorders/drug therapy
Male

@article {pmid40094842,
year = {2025},
author = {Aghasizadeh Sherbaf, R and Kaposvári, GM and Nagy, K and Pakáski, M and Gajdács, M and Matusovits, D and Baráth, Z},
title = {Oral Health Status and Factors Associated with Oral Health in Patients with Alzheimer's Disease: A Matched Case-Control Observational Study.},
journal = {Journal of clinical medicine},
volume = {14},
number = {5},
pages = {},
doi = {10.3390/jcm14051412},
pmid = {40094842},
issn = {2077-0383},
abstract = {Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease, ranking as the seventh leading cause of death in both sexes. There is increasing awareness of the role of chronic periodontal disease and severe tooth loss as a modifiable risk factor for developing AD. The aim of the present observational study was to assess AD patients with non-affected healthy controls in the context of their dental and periodontal health outcomes; additionally, the potential impact of anamnestic factors and lifestyle habits on oral health outcomes was also studied. Methods: A total of n = 41 AD patients receiving treatment at the Department of Psychiatry, University of Szeged, were compared with n = 41 age- and gender-matched controls from individuals seeking dental treatment and from retirement homes (mean age was 83.32 ± 7.82 years). Dental and periodontal status indices were assessed according to World Health Organization (WHO) criteria. Results: Overall, 51.2%, 68.3%, and 87.8% of AD patients received mood stabilizers, drugs for their non-cognitive symptoms and cognitive symptoms, respectively. Severe tooth loss was observed in 43.9% of AD patients and 56.1% of controls, respectively. There were no significant differences among AD patients and controls regarding the dental status indices studied (p > 0.05 for all indicators). AD patients had significantly higher plaque indices (%) (59.06 ± 15.45 vs. 41.35 ± 7.97; p < 0.001), bleeding on probing (BOP%) (62.65 ± 12.00 vs. 40.12 ± 10.86; p < 0.001), pocket depth [PD] (2.63 ± 0.56 vs. 2.29 ± 0.13; p = 0.002) and attachment loss [AL] (2.85 ± 0.79 vs. 2.39 ± 0.41; p = 0.026) values, compared to controls. Smoking (vs. non-smokers; 56.28 ± 12.36 vs. 51.40 ± 13.23, p = 0.038) and consumption of alcohol (vs. non-drinkers; 58.68 ± 9.86 vs. 54.78 ± 14.86, p = 0.040) were associated with higher plaque indices [%], while no similar effects were shown for dental status parameters (p > 0.05). In contrast, coffee intake and vitamin supplement use had no significant effect on dental or periodontal status parameters (p > 0.05 in all cases). Conclusions: The results of our study underscore the substantial treatment needs of AD patients, calling for heightened awareness among dental healthcare professionals.},
}

@article {pmid40093888,
year = {2025},
author = {Pees, A and Morrone, CD and Tong, J and Rong, J and Shao, T and Wear, D and Liang, SH and Yu, WH and Vasdev, N},
title = {Sex- and age-specific sensitivities of the endocannabinoid system in Alzheimer's disease revealed by PET imaging with [[18]F]FMPEP-d 2 and [[18]F]MAGL-2102.},
journal = {Theranostics},
volume = {15},
number = {8},
pages = {3368-3385},
pmid = {40093888},
issn = {1838-7640},
mesh = {Animals ; *Alzheimer Disease/diagnostic imaging/metabolism ; Female ; Male ; Mice ; *Brain/diagnostic imaging/metabolism ; *Endocannabinoids/metabolism ; *Disease Models, Animal ; *Positron-Emission Tomography/methods ; Monoacylglycerol Lipases/metabolism/genetics/antagonists & inhibitors ; Mice, Transgenic ; Fluorine Radioisotopes ; Positron Emission Tomography Computed Tomography/methods ; Receptor, Cannabinoid, CB1/metabolism/genetics ; Humans ; Sex Factors ; Age Factors ; Radiopharmaceuticals ; Amyloid beta-Protein Precursor/metabolism/genetics ; Autoradiography ; },
abstract = {The endocannabinoid system is a critical brain signaling pathway that is dysregulated in various brain disorders, including Alzheimer's disease (AD). Cannabinoid-targeted therapies and imaging approaches have gained increasing interest; however, the biological impact of the endocannabinoid system in disease needs further validation. We aimed to study changes in cannabinoid receptor 1 (CB1) and monoacylglycerol lipase (MAGL), components of endocannabinoid signaling and degradation, in a mouse model of AD by PET imaging. Methods: [[18]F]FMPEP-d 2 and [[18]F]MAGL-2102 were produced on a commercial radiosynthesis module. PET-CT images with both tracers were acquired in a knock-in mouse model of AD bearing mutated human amyloid precursor protein (App[NL-G-F]) at 3 ages, and compared to wild-type mice. Excised brains were used for in vitro autoradiography with [[18]F]FMPEP-d 2 and [[18]F]MAGL-2102, immunofluorescence, and western blotting. Male wild-type and 5xFAD mice were chronically treated with MAGL inhibitor JZL184 and imaged with [[18]F]MAGL-2102 two days after ending treatment. Results: PET imaging showed sex-, age- and genotype-dependent changes in CB1 and MAGL availability. At 4-months (early-stage β-amyloid pathology), female App[NL-G-F] mice had lower CB1 availability, and MAGL availability was increased in male App[NL-G-F] , compared to wild-types. At 8-months, no genotype differences in CB1 were observed, yet MAGL availability was reduced in App[NL-G-F] frontal cortex, and male App[NL-G-F] mice exhibited higher MAGL than transgenic females brain-wide. At 12-months (late-stage β-amyloid pathology), significantly lower uptake of [[18]F]FMPEP-d 2 was observed in App[NL-G-F] compared to wild-type, with no changes in [[18]F]MAGL-2102 binding. App[NL-G-F] plaque staging was confirmed by Thioflavin-S staining. Imaging findings were supplemented by autoradiography, immunofluorescence, and western blots. [[18]F]MAGL-2102 availability was responsive to target engagement of the MAGL inhibitor JZL184 in wild-type and 5xFAD mice. Conclusions: The present study showed dynamic age-, sex- and pathology-related changes in CB1 and MAGL availability from early-stage β-amyloid pathology, suggesting that the endocannabinoid system is a useful target for diagnostics and treatment of AD. Finally, these results highlight that endocannabinoid sex differences should be considered in diagnostics and drug development.},
}

Animals
*Alzheimer Disease/diagnostic imaging/metabolism
Female
Male
Mice
*Brain/diagnostic imaging/metabolism
*Endocannabinoids/metabolism
*Disease Models, Animal
*Positron-Emission Tomography/methods
Monoacylglycerol Lipases/metabolism/genetics/antagonists & inhibitors
Mice, Transgenic
Fluorine Radioisotopes
Positron Emission Tomography Computed Tomography/methods
Receptor, Cannabinoid, CB1/metabolism/genetics
Humans
Sex Factors
Age Factors
Radiopharmaceuticals
Amyloid beta-Protein Precursor/metabolism/genetics
Autoradiography

@article {pmid40093519,
year = {2025},
author = {Atta, AM and Rihan, N and Abdelwaly, AM and Nafie, MS and Elgawish, MS and Moustafa, SM and Helal, MA and Darwish, KM},
title = {Development, biological evaluation, and molecular modelling of novel isocytosine and guanidine derivatives as BACE1 inhibitors using a fragment growing strategy.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {40093519},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition characterized by significant synaptic loss and neuronal death in brain regions critical for cognitive functions. The disease is characterized by the formation of amyloid plaques, which are extracellular constructs consisting mainly of aggregated Aβ42. The latter is a peptide formed by the proteolytic cleavage of β-amyloid precursor protein (APP) by two enzymes, β- and γ-secretase. Therefore, inhibition of the aspartic protease β-secretase (BACE1) is considered a promising therapeutic approach for the treatment and prevention of Alzheimer's disease. Unfortunately, a limited number of β-secretase inhibitors have reached human trials and eventually failed due to inconclusive therapeutic and/or safety profiles. In this study, we developed drug-like molecules with a β-secretase inhibitory activity using a fragment growing strategy on isocytosine and acyl guanidine warheads. Our approach is based on optimizing the hydrophobic part of the molecules to obtain a conformationally restrained scaffold complementary to the hydrophobic pockets within the enzyme active site. We developed 32 compounds with promising in vitro inhibitory activity against BACE1 down to sub-micromolar IC50. Docking simulation studies were performed to understand the mode of binding of the prepared compounds. We demonstrated that compounds with superior activities, such as 16b and 16g, are able to provide the best balance between the steric shape and position of the polar substituent for achieving preferential anchoring into the S1, S3, S1', and S2' sub-pockets. Further, in vivo characterization of selected drug-like candidates of the benzimidazole series AMK-IV, namely 16a and 16k, demonstrated their ability to reduce oxidation stress and their safety within brain and liver tissues.},
}

@article {pmid40093146,
year = {2025},
author = {Wu, P and Chen, D and Wang, F and Lu, K and Sigurdsson, EM and Jin, C},
title = {Formaldehyde induces and promotes Alzheimer's disease pathologies in a 3D human neural cell culture system.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.02.27.640690},
pmid = {40093146},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) arises from complex multilevel interactions between genetic, epigenetic, and environmental factors. Recent studies suggest that exposure to the environmental and occupational toxicant formaldehyde (FA) may play a significant role in AD development. However, the effects of FA exposure on Aβ and tau pathologies in human neural cell 3D culture systems remain unexplored. To investigate FA's role in AD initiation, we differentiated 3D-cultured immortalized human neural progenitor ReN cells (ReNcell VM) into neurons and glial cells, followed by FA treatment. FA exposure for 12 weeks resulted in a dose-dependent increase in Aβ40, Aβ42, and phosphorylated tau levels. To further examine FA's role in AD progression, we established a 3D human neural cell culture AD model by transfecting ReN cells with AD-related mutant genes, including mutant APP and PSEN1, which recapitulate key AD pathological events. Our findings demonstrate that FA exposure significantly elevated Aβ40, Aβ42, and phosphorylated tau levels in this 3D-cultured AD model. These results suggest that FA exposure contributes to the initiation and progression of AD pathology in 3D-cultured human neural cells.},
}

@article {pmid40092207,
year = {2025},
author = {Wihadmadyatami, H and Zulfikar, MA and Herawati, H and Karnati, S and Saragih, GR and Aliffia, D and Pratama, DAOA and Handayani, N and Kustiati, U and Tirtosari, DR and Tjahjono, Y},
title = {Neuroprotection effect of bovine umbilical mesenchymal stem cell-conditioned medium on the rat model of Alzheimer's disease mediated by upregulation of BDNF and NGF and downregulation of TNF-α and IL-1β.},
journal = {Open veterinary journal},
volume = {15},
number = {1},
pages = {151-161},
pmid = {40092207},
issn = {2218-6050},
mesh = {Animals ; *Alzheimer Disease/metabolism/veterinary/therapy ; Rats ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Male ; *Nerve Growth Factor/metabolism/genetics ; *Interleukin-1beta/metabolism ; *Tumor Necrosis Factor-alpha/metabolism/genetics ; *Mesenchymal Stem Cells ; Culture Media, Conditioned/pharmacology ; *Disease Models, Animal ; Cattle ; *Up-Regulation/drug effects ; Down-Regulation/drug effects ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) are distinguished by impairment and depletion of nerve cells; one of the most common NDDs is Alzheimer's disease (AD), which can appear in early onset or late onset. In recent years, the secretome or conditioned medium of mesenchymal stem cells has provided new hope for improving conditions and preventing AD. One of the secretomes is bovine umbilical mesenchymal stem cells-conditioned medium (BUMSC-CM), where BUMSC is predicted to promote neuronal proliferation potentially.

AIM: This study analyzes the therapeutic efficiency of conditioned medium or secretome produced from BUMSC-CM in treating neurodegeneration in animal models of AD.

METHODS: Five groups consisting of 12 male rats were assigned: untreated (Group A, n = 5), positive control group given normal saline 1 ml/100 g BW (Group B, n = 5), AD rats model followed by Donepezil treatment (Group C, n = 5), AD rats model with BUMSC-CM 0.2 ml/kg BW post-trimethyltin (TMT) induction (Group D, n = 5), and AD rats model with BUMSC-CM 0.5 ml/kg BW post-TMT induction (Group E, n = 5). The brain samples were analyzed for neuronal density using cresyl violet staining. The expression and activity of brain-derived neurotrophic factor (BDNF) were analyzed by ELISA; in addition, interleukin 1beta (IL-1β), tumor necrotic factor-alpha (TNF-α), and neural growth factor (NGF) were analyzed by quantitative polymerase chain reaction. Interactions between the main substances of BUMSC-CM and beta-amyloid protein were visualized using in silico molecular docking.

RESULTS: Our result demonstrated that BUMSC-CM with the dosage of 0.5 ml/kg BW significantly increased BDNF concentration. We also found that BUMSC-CM with dosage 0.2 ml/kg BW and 0.5 ml/kg BW down-regulated IL-1β and TNF-α and upregulated NGF expression. Additionally, the number of neurons in AD rats post-treated with BUMSC-CM was significantly increasing. Furthermore, the amino acids in BUMSC-CM, including isoleucine, leucine, and valine, bind to the amyloid beta protein via interactions that are hydrophobic and hydrogen-bonded.

CONCLUSION: In this study, the neuroprotective potential of BUMSC-CM was demonstrated by its ability to upregulate BDNF and NGF while downregulating IL-1β and TNF-α. Additionally, BUMSC-CM showed potential to promote neuron proliferation in the hippocampus regions of a rat AD model. The main constituents in BUMSC-CM adhere to amyloid beta protein, hence diminishing the likelihood of ND disorders, specifically AD.},
}

Animals
*Alzheimer Disease/metabolism/veterinary/therapy
Rats
*Brain-Derived Neurotrophic Factor/metabolism/genetics
Male
*Nerve Growth Factor/metabolism/genetics
*Interleukin-1beta/metabolism
*Tumor Necrosis Factor-alpha/metabolism/genetics
*Mesenchymal Stem Cells
Culture Media, Conditioned/pharmacology
*Disease Models, Animal
Cattle
*Up-Regulation/drug effects
Down-Regulation/drug effects
Neuroprotective Agents/pharmacology

@article {pmid40092057,
year = {2025},
author = {Reddy, NK},
title = {Redefining disease in the age of blood-based biomarkers.},
journal = {Frontiers in sociology},
volume = {10},
number = {},
pages = {1533429},
pmid = {40092057},
issn = {2297-7775},
abstract = {This article explores the sociological and ethical implications of redefining disease in the era of advanced diagnostic technologies, with a focus on blood-based biomarkers. Drawing from Foucault's concept of medicalization and Illich's critique of disease mongering, it highlights how diagnostic expansions, driven by corporate and institutional influences, are reshaping the boundaries of health and disease. Advances such as blood assays for Alzheimer's and Parkinson's diseases, liquid biopsies in oncology, and biomarkers for depression and diabetes, while promising, raise concerns about premature diagnoses and overtreatment. The influence of pharmaceutical and insurance industries on diagnostic criteria, as seen in the ICD updates, underscores the need to address conflicts of interest and regulatory gaps. Case studies on Alzheimer's and Parkinson's reveal how these changes could benefit stakeholders at the expense of patient welfare. The article calls for ethical oversight, stricter regulation, and research into the population-level efficacy of diagnostic and treatment protocols.},
}

@article {pmid40091636,
year = {2025},
author = {Lee, EH and Kwon, H and Park, SY and Park, JY and Hong, JH and Paeng, JW and Kim, YK and Han, PL},
title = {Sphingomonas Paucimobilis-derived Extracellular Vesicles Reverse Aβ-induced Dysregulation of Neurotrophic Factors, Mitochondrial Function, and Inflammatory Factors through MeCP2-mediated Mechanism.},
journal = {Experimental neurobiology},
volume = {34},
number = {1},
pages = {20-33},
doi = {10.5607/en25001},
pmid = {40091636},
issn = {1226-2560},
abstract = {Recent studies have shown an increased abundance of Sphingomonas paucimobilis, an aerobic, Gram-negative bacterium with a distinctive cell envelope rich in glycosphingolipids, within the gut microbiome of individuals with Alzheimer Disease (AD). However, the fact that S. paucimobilis is a well-known pathogen associated with nosocomial infections presents a significant challenge in investigating whether its presence in the gut microbiome is detrimental or beneficial, particularly in the context of AD. This study examines the impact of S. paucimobilis-derived extracellular vesicles (Spa-EV) on Aβ-induced pathology in cellular and animal models of AD. Microarray analysis reveals that Spa-EV treatment modulates Aβ42-induced alterations in gene expression in both HT22 neuronal cells and BV2 microglia cells. Among the genes significantly affected by Spa-EV, notable examples include Bdnf, Nt3/4, and Trkb, which are key players of neurotrophic signaling; Pgc1α, an upstream regulator of mitochondrial biogenesis; Mecp2 and Sirt1, epigenetic factors that regulate numerous gene expressions; and Il1β, Tnfα, and Nfκb-p65, which are associated with neuroinflammation. Remarkably, Spa-EV effectively reverses Aβ42-induced alteration in the expression of these genes through the upregulation of Mecp2. Furthermore, administration of Spa-EV in Tg-APP/PS1 mice restores the reduced expression of neurotrophic factors, Pgc1α, MeCP2, and Sirt1, while suppressing the increased expression of proinflammatory genes in the brain. Our results indicate that Spa-EV has the potential to reverse Aβ-induced dysregulation of gene expression in neuronal and microglial cells. These alterations encompass those essential for neurotrophic signaling and neuronal plasticity, mitochondrial function, and the regulation of inflammatory processes.},
}

@article {pmid40090653,
year = {2025},
author = {Zaater, MA and El Kerdawy, AM and Mahmoud, WR and Abou-Seri, SM},
title = {Going beyond ATP binding site as a novel inhibitor design strategy for tau protein kinases in the treatment of alzheimer's disease: A review.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {142141},
doi = {10.1016/j.ijbiomac.2025.142141},
pmid = {40090653},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is among the top mortality causing diseases worldwide. The presence of extracellular β-amyloidosis, as well as intraneuronal neurofibrillary aggregates of the abnormally hyperphosphorylated tau protein are two major characteristics of AD. Targeting protein kinases that are involved in the disease pathways has been a common approach in the fight against AD. Unfortunately, most kinase inhibitors currently available target the adenosine triphosphate (ATP)- binding site, which has proven unsuccessful due to issues with selectivity and resistance. As a result, a pressing need to find other alternative sites beyond the ATP- binding site has profoundly evolved. In this review, we will showcase some case studies of inhibitors of tau protein kinases acting beyond ATP binding site which have shown promising results in alleviating AD.},
}

@article {pmid40090428,
year = {2025},
author = {Shete, P and Misar, A and Ugale, V and Suryavanshi, K and Ghatpande, N and Waghole, R and Datar, M and Shravage, B and Kulkarni, P},
title = {Multi-target activity of ethanolic extract of Crinum woodrowii Baker for the treatment of Alzheimer's disease.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {119622},
doi = {10.1016/j.jep.2025.119622},
pmid = {40090428},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease affecting mental ability and neurocognitive functions. Crinum woodrowii Baker (C. woodrowii) is an endemic plant with significant ethnobotanical potential against neurological and inflammatory conditions with a characteristic improvement of cognitive functions.

AIM OF THE STUDY: To assess the anti-AD potential of C. woodrowii extract through in-vitro assays and preclinical in-vivo screening and to validate its neuroprotective effect by biochemical and histopathological analysis.

MATERIALS AND METHODS: Herein, galantamine contents of the ethanolic extract of C. woodrowii were quantified using HPLC and LCMS. Further, the extract was examined for in-vitro cytotoxicity, anti-inflammatory, anti-cholinesterase activities, and in-vivo neuropharmacological studies.

RESULTS: The extract exhibited low cytotoxicity on RAW 264.7 cells and the inhibition of LPS-induced nitric oxide production. The extract also showed anti-cholinesterase activities. The treatment with extract significantly rescued the rough eye phenotype in the Drosophila model of AD. In neuropharmacological screening, the extract showed no symptoms of acute oral toxicity in rats. The extract significantly reversed scopolamine-induced memory deficit in mice and improved their learning ability with memory retention in exteroceptive behavioral models. The pretreatment of mice with extract reinstated the elevated brain acetylcholinesterase, lipid peroxidation, and reduced glutathione levels due to scopolamine and aging. The extract also restored the altered superoxide dismutase and catalase levels. The extract alleviated neuronal tissue damage caused by the scopolamine, as indicated by the histological analyses of the brain.

CONCLUSION: Our findings suggested that the C. woodrowii extract has neuroprotective properties and ameliorates cognitive dysfunction and hence could be explored further as a potential neurotherapeutics for treating AD.},
}

@article {pmid40090398,
year = {2025},
author = {Wang, A and Zhang, F and Zhang, W and Gong, J and Sun, X},
title = {PPM1D ameliorates Alzheimer's disease by promoting mitophagy.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115218},
doi = {10.1016/j.expneurol.2025.115218},
pmid = {40090398},
issn = {1090-2430},
abstract = {Mitochondrial autophagy (mitophagy) plays an essential role in the maintenance of mitochondrial homeostasis. Defective mitophagy triggered by amyloid beta (Aβ) is linked to neuronal deterioration and neurodegeneration in Alzheimer's disease (AD). However, the molecular mechanism underlying the defective mitophagy in AD is still not fully illustrated. Protein phosphatase Mn[2+]/Mg[2+]-dependent 1D (PPM1D) triggers autophagy in mouse embryonic fibroblasts. Downregulated PPM1D in the hippocampus of APP/PS1 mice. This study aims to investigate the role of PPM1D in the progression of AD. Here, APP/PS1 mice were used to mimic AD, and rAAV2 vectors expressing PPM1D were injected into the bilateral hippocampus. In vitro, the mouse hippocampal neuron cell line HT22 was stimulated by Aβ1-42 to trigger neuronal damage. High PPM1D expression alleviated the impairments of spatial cognition and memory in APP/PS1 mice. Additionally, PPM1D enhanced autophagosome formation, lysosomal degradation of impaired mitochondria, amyloid plaque deposition, and neuronal degeneration and apoptosis in the hippocampus of APP/PS1 mice. Similar effects of PPM1D on neuronal apoptosis and mitophagy were observed in Aβ1-42-treated HT22 cells, and the effects could be reversed by the mitophagy inhibitor cyclosporine A. In conclusion, PPM1D facilitates mitophagy to inhibit the progression of AD-like disease. Taken together, the present work uncovers defective mitophagy in AD may be associated with down-regulated PPM1D, and PPM1D may be a potential therapeutic target for AD treatment.},
}

@article {pmid40089260,
year = {2025},
author = {Singh, R and Prerna, and Bansal, R},
title = {Neuroprotective potential of 17-oximino-16-arylidene steroids: In vivo and in silico investigations.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177467},
doi = {10.1016/j.ejphar.2025.177467},
pmid = {40089260},
issn = {1879-0712},
abstract = {Several recent literature reports indicate the strong neuroprotective potential of synthetic heterosteroids, still search for potent, safer and effective neuroprotective steroidal molecules continues. In the current study, a new series of 17-oximino-16-substituted steroids (1-8) has been evaluated in MPTP-induced Parkinson's disease in mice and amyloid-β induced Alzheimer's disease in rats with an intention to discover an effective and efficient neuroprotective molecule. Behavioural studies followed by histopathological and estimation of the several neuroinflammatory biochemical parameters such as acetylcholinesterase, lipid peroxide, reactive oxygen, and nitric oxide species were carried out. A significant improvement in cognitive and locomotive dysfunctions was observed after treatment with these compounds. In silico molecular docking and simulation studies also correlated with the neuroprotective effects of the steroidal oximes 1-8 as strong binding affinities for TNF-α, IL-1β, AChE and β-secretase were seen. Among all the compounds, 4-pyridylidene (3) and 2-pyridylidene (1) substituted steroids displayed maximum neuroprotective efficacy in animal models of Parkinson's disease and Alzheimer's disease, respectively, and produced effects better than standard drugs. Hence, a new series of 16-arylideno-17-oximino steroids has been identified as potent neuroprotective agents which could be further explored structurally and clinically to discover and develop lead drug molecules useful for the treatment of Parkinson's and Alzheimer's disease.},
}

@article {pmid40089090,
year = {2025},
author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X},
title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.},
journal = {Cellular signalling},
volume = {131},
number = {},
pages = {111715},
doi = {10.1016/j.cellsig.2025.111715},
pmid = {40089090},
issn = {1873-3913},
abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.},
}

@article {pmid40089052,
year = {2025},
author = {Anna, P and Gianluigi, D and Simone, P and Mia, B and Martina, M and Camilla, M and Cristina, F and Luca Giuseppe, DC and Chris, E and Ettore, M and Federico, S and Massimo, V},
title = {Increasing nitric oxide availability via ingestion of nitrate-rich beetroot juice improves vascular responsiveness in individuals with Alzheimer's Disease.},
journal = {Nitric oxide : biology and chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.niox.2025.03.001},
pmid = {40089052},
issn = {1089-8611},
abstract = {Poor vascular function and reduced nitric oxide (NO)-bioavailability have been recognized to be involved in aging and Alzheimer's Disease (AD). A non-pharmacological treatment that is gaining clinical interest in the context of vascular function is dietary inorganic nitrate () supplementation which increases NO-bioavailability through the -nitrite () - NO pathway. This treatment has been demonstrated to improve vascular function in several clinical populations, but no study has investigated the effects in individuals with AD. Therefore, changes in plasma and and vascular responsiveness (hyperemic response to single-passive leg movement (ΔPLM)) were measured in individuals with AD (n=10, 76±9 years), healthy elderly (OLD, n=10, 75±6 years), and young individuals (YN, n=10, 25±4 years) before (T0) and hourly for 4 hours (T1, T2, T3, and T4) after ingestion of either -rich beetroot juice (BR) or a placebo (PLA). No changes in and , nor ΔPLM were detected in any group following PLA intake. Plasma and increased significantly in all three groups at T1 (p<0.001) and remained elevated for the remainder of the trial. The same trend was found in ΔPLM, which significantly increased in all three groups over the time (p<0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to YN (p<0.001) and OLD (p<0.001). These data suggest that AD-individuals included in this study were able to reduce to and to increase NO-mediated vascular responsiveness as non-AD-individuals. Other mechanisms, beyond NO-bioavailability, may be involved in vascular dysfunction in patients with AD. This research suggests that an acute administration of inorganic nitrate is not enough to revert chronically adapted vascular properties and completely restore vascular responsiveness in AD.},
}

@article {pmid40089002,
year = {2025},
author = {da Silva, EA and de Abreu, JFF and Penitente, AR and Fernandes, J and Bertolucci, PHF and Longo, BM and Arida, RM},
title = {Effects of resistance exercise on behavioral and molecular changes in transgenic female mice for Alzheimer's disease in early and advanced stages.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115217},
doi = {10.1016/j.expneurol.2025.115217},
pmid = {40089002},
issn = {1090-2430},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a neurodegenerative condition that affects memory and cognition, with a higher prevalence in women. Given the lack of effective treatment, physical activity stands out as a complementary approach to prevent or delay disease progression. While numerous studies on humans and animals indicate that aerobic exercise induces brain changes, the impact of resistance exercise (RE) on AD is not fully understood.

OBJECTIVE: This study aimed to investigate the behavioral and molecular changes induced by RE in female transgenic mice with AD at the early and advanced stages of the disease.

MATERIALS AND METHODS: Adult (initial phase - 7 to 8 months of age, n = 32) and adult/elderly (advanced phase - 22 to 23 months of age, n = 32) female mice (2xTg-AD) for the APPSWE/PS1dE9 mutation were subjected to a four-week RE protocol. Mobility, anxiety-like behavior, long-term memory (LTM), and depressive-like behavior were assessed. Beta-amyloid (βA) and cytokines were quantified using the ELISA technique.

RESULTS: There was a progressive increase in strength in both trained groups at different ages. RE reversed memory deficits only in adult AD animals and the anxiety-like behavior only in adult/elderly AD animals. RE reversed depressive-like behavior in adult and adult/elderly AD animals. RE reduced βA only in adult AD animals. RE modified the expression of several cytokines in animals in the early and advanced stage of AD.

CONCLUSION: RE can be a promising strategy to minimize the deleterious effects of AD; however, its effectiveness may be more limited to the early stages of the disease.},
}

@article {pmid40093660,
year = {2023},
author = {He, Z and Dieciuc, M and Carr, D and Chakraborty, S and Singh, A and Fowe, IE and Zhang, S and Lustria, MLA and Terracciano, A and Charness, N and Boot, WR},
title = {New Opportunities for the Early Detection and Treatment of Cognitive Decline: Adherence Challenges and the Promise of Smart and Person-Centered Technologies.},
journal = {BMC digital health},
volume = {1},
number = {},
pages = {},
pmid = {40093660},
issn = {2731-684X},
abstract = {Early detection of age-related cognitive decline has transformative potential to advance the scientific understanding of cognitive impairments and possible treatments by identifying relevant participants for clinical trials. Furthermore, early detection is also key to early intervention once effective treatments have been developed. Novel approaches to the early detection of cognitive decline, for example through assessments administered via mobile apps, may require frequent home testing which can present adherence challenges. And, once decline has been detected, treatment might require frequent engagement with behavioral and/or lifestyle interventions (e.g., cognitive training), which present their own challenges with respect to adherence. We discuss state-of-the-art approaches to the early detection and treatment of cognitive decline, adherence challenges associated with these approaches, and the promise of smart and person-centered technologies to tackle adherence challenges. Specifically, we highlight prior and ongoing work conducted as part of the Adherence Promotion with Person-centered Technology (APPT) project, and how completed work will contribute to the design and development of a just-in-time, tailored, smart reminder system that infers participants' contexts and motivations, and how ongoing work might build toward a reminder system that incorporates dynamic machine learning algorithms capable of predicting and preventing adherence lapses before they happen. APPT activities and findings will have implications not just for cognitive assessment and training, but for technology-mediated adherence-support systems to facilitate physical exercise, nutrition, medication management, telehealth, and social connectivity, with the potential to broadly improve the engagement, health, and well-being of older adults.},
}

@article {pmid40088370,
year = {2025},
author = {Bhatia, V and Vikram, V and Chandel, A and Rattan, A},
title = {Interplay between PI3k/AKT signaling and caspase pathway in Alzheimer disease: mechanism and therapeutic implications.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40088370},
issn = {1568-5608},
abstract = {Alzheimer's disease, a neurodegenerative disorder, is characterized by cognitive impairment, neuronal loss, and synaptic dysfunction. The interplay between the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and the caspase-mediated apoptotic cascade plays a pivotal role in its progression. The signaling pathway responsible for neuronal survival also regulates synaptic plasticity and resistance to oxidative stress, whereas caspase activation accelerates neurodegeneration by triggering cell death and inflammation. Dysregulation of these pathways leads to amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and mitochondrial dysfunction, creating a negative feedback loop and accelerating disease progression. Emerging treatment methods that target PI3K/AKT activation and caspase inhibition have showed promise in preclinical models, preventing neuronal apoptosis while retaining cognitive function. This review investigates the molecular processes driving PI3K/AKT and caspase crosstalk, their significance in Alzheimer's disease, and prospective therapeutic strategies aiming at regulating these pathways to improve disease outcomes.},
}

@article {pmid40087862,
year = {2025},
author = {Balantzategi, U and Gaminde-Blasco, A and Kearns, CA and Bayón-Cordero, L and Sánchez-Gómez, MV and Zugaza, JL and Appel, B and Alberdi, E},
title = {Amyloid-β Dysregulates Oligodendroglial Lineage Cell Dynamics and Myelination via PKC in the Zebrafish Spinal Cord.},
journal = {Glia},
volume = {},
number = {},
pages = {},
doi = {10.1002/glia.70015},
pmid = {40087862},
issn = {1098-1136},
support = {FPU17/04891//Ministerio de Ciencia, Innovación y Universidades/ ; PID2019-108465RB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2022-140236OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; IT1551-22//Eusko Jaurlaritza/ ; PIBA_2020_1_0012//Eusko Jaurlaritza/ ; PRE_2019_1_0132//Eusko Jaurlaritza/ ; PRE_2019_1_0317//Eusko Jaurlaritza/ ; BIO22/ALZ/014//Berrikuntza + Ikerketa + Osasuna Eusko Fundazioa/ ; NS095679/NH/NIH HHS/United States ; R35NS122191/NH/NIH HHS/United States ; },
abstract = {Soluble forms of amyloid-β (Aβ) peptide have been proposed as candidates to induce oligodendrocyte (OL) and myelin dysfunctions in the early stages of Alzheimer's disease (AD) pathology. Nevertheless, little is known about how Aβ affects OL differentiation and myelination in vivo, and the underlying molecular mechanisms. In this study, we explored the effects of a brain intraventricular injection of Aβ on OLs and myelin in the developing spinal cord of zebrafish larvae. Using quantitative fluorescent in situ RNA hybridization assays, we demonstrated that Aβ altered myrf and mbp mRNA levels and the regional distribution of mbp during larval development, suggesting an early differentiation of OLs. Through live imaging of Tg(myrf:mScarlet) and Tg(mbpa:tagRFP) zebrafish lines, both crossed with Tg(olig2:EGFP), we found that Aβ increased the number of myrf[+] and mbp[+] OLs in the dorsal spinal cord at 72 hpf and 5 dpf, respectively, without affecting total cell numbers. Furthermore, Aβ also increased the number of Sox10[+]cells, myelin sheaths per OL, and the number of myelinated axons in the dorsal spinal cord at 8 dpf compared to vehicle-injected control animals. Interestingly, the treatment of Aβ-injected zebrafish with the pan-PKC inhibitor Gö6983 restored the aforementioned alterations in OLs and myelin to control levels. Altogether, not only do we demonstrate that Aβ induces a precocious oligodendroglial differentiation leading to dysregulated myelination, but we also identified PKC as a key player in Aβ-induced pathology.},
}

@article {pmid40087766,
year = {2025},
author = {Tocci, D and Fogel, M and Gupta, V and Kim, P and Latimer, J and Adlimoghaddam, A and Robison, LS and Albensi, BC},
title = {Beyond expectations: investigating nilotinib's potential in attenuating neurodegeneration in alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {60},
pmid = {40087766},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Pyrimidines/therapeutic use/pharmacology ; Animals ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), pose a formidable global challenge. While therapeutic options are available, their limitations are significant, necessitating the development of innovative treatment approaches. Here, we highlight the importance of repurposing drugs and discuss the future of drug treatments for AD. We review the potential of tyrosine kinase inhibitors (TKI) for mitigating AD pathology and symptoms, as well as neurodegenerative processes more broadly. We focus on nilotinib, a selective BCR-ABL tyrosine kinase inhibitor, which has unique mechanisms of action involving the modulation of cell responses and removal of toxic proteins associated with AD pathogenesis. Encouraging studies have demonstrated its efficacy, calling for further investigation through clinical trials to assess its potential in various neurodegenerative conditions. However, despite these promising preclinical findings, no clinical studies have yet conclusively demonstrated its efficacy in treating AD. Considering the future directions in AD research, personalized medicine approaches hold promise by incorporating patient-specific factors, including sex and gender differences, to tailor nilotinib treatment for improved efficacy and safety profiles.},
}

Humans
*Alzheimer Disease/drug therapy
*Pyrimidines/therapeutic use/pharmacology
Animals
*Protein Kinase Inhibitors/therapeutic use/pharmacology

@article {pmid40087204,
year = {2025},
author = {Lin, D and Howard, A and Raihane, AS and Di Napoli, M and Cáceres, E and Ortiz, M and Davis, J and Abdelrahman, AN and Divani, AA},
title = {Traumatic Brain Injury and Gut Microbiome: The Role of the Gut-Brain Axis in Neurodegenerative Processes.},
journal = {Current neurology and neuroscience reports},
volume = {25},
number = {1},
pages = {23},
pmid = {40087204},
issn = {1534-6293},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/microbiology/physiopathology ; *Brain Injuries, Traumatic/microbiology/physiopathology/complications ; *Brain-Gut Axis/physiology ; Animals ; Dysbiosis ; Brain/physiopathology ; },
abstract = {PURPOSE OF REVIEW: A deeper understanding of the communication network between the gut microbiome and the central nervous system, termed the gut-brain axis (GBA), has revealed new potential targets for intervention to prevent the development of neurodegenerative disease associated with tramatic brain injury (TBI). This review aims to comprehensively examine the role of GBA post-traumatic brain injury (TBI).

RECENT FINDINGS: The GBA functions through neural, metabolic, immune, and endocrine systems, creating bidirectional signaling pathways that modulate brain and gastrointestinal (GI) tract physiology. TBI perturbs these signaling pathways, producing pathophysiological feedback loops in the GBA leading to dysbiosis (i.e., a perturbed gut microbiome, impaired brain-blood barrier, impaired intestinal epithelial barrier (i.e., "leaky gut"), and a maladaptive, systemic inflammatory response. Damage to the CNS associated with TBI leads to GI dysmotility, which promotes small intestinal bacterial overgrowth (SIBO). SIBO has been associated with the early stages of neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Many of the bacteria associated with this overgrowth promote inflammation and, in rodent models, have been shown to compromise the structural integrity of the intestinal mucosal barrier, causing malabsorption of essential nutrients and further exacerbating dysbiosis. TBI-induced pathophysiology is strongly associated with an increased risk of neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, which represents a significant public health burden and challenge for patients and their families. A healthy gut microbiome has been shown to promote improved recovery from TBI and prevent the development of neurodegenerative disease, as well as other chronic complications. The role of the gut microbiome in brain health post-TBI demonstrates the potential for microbiome-targeted interventions to mitigate TBI-associated comorbidities. Promising new evidence on prebiotics, probiotics, diet, and fecal microbiota transplantation may lead to new therapeutic options for improving the quality of life for patients with TBI. Still, many of these preliminary findings must be explored further in clinical settings. This review covers the current understanding of the GBA in the setting of TBI and how the gut microbiome may provide a novel therapeutic target for treatment in this patient population.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Neurodegenerative Diseases/microbiology/physiopathology
*Brain Injuries, Traumatic/microbiology/physiopathology/complications
*Brain-Gut Axis/physiology
Animals
Dysbiosis
Brain/physiopathology

@article {pmid40086955,
year = {2025},
author = {Chin, WL and Lee, BH and Hsu, QY and Hou, CY and Pai, MC and Lin, CW and Hsu, WH},
title = {Small intestine-residing probiotics suppress neurotoxic bile acid production via extracellular vesicle-mediated inhibition of Clostridium scindens.},
journal = {Food research international (Ottawa, Ont.)},
volume = {207},
number = {},
pages = {116049},
doi = {10.1016/j.foodres.2025.116049},
pmid = {40086955},
issn = {1873-7145},
mesh = {Animals ; *Probiotics/pharmacology ; *Clostridium/metabolism ; *Intestine, Small/microbiology/metabolism ; *Gastrointestinal Microbiome ; *Bile Acids and Salts/metabolism ; Mice ; *Extracellular Vesicles/metabolism ; *Mice, Transgenic ; Lactobacillus johnsonii/metabolism ; Lithocholic Acid/metabolism ; Humans ; Alzheimer Disease/metabolism/microbiology ; },
abstract = {Dysbiosis in gut microbiota and abnormalities in bile acids have been linked to neurodegenerative diseases. While many studies have focused on the relationship between colonic bacteria and Alzheimer's disease (AD), this study propose that alterations in the small intestine microbiota may play a more critical role. This is because the small intestine is pivotal in recycling bile acids through enterohepatic circulation. This study uses amyloid precursor protein knock-in (APP[NL-G-F/NL-G-F]) transgenic mice to investigate the association between intestinal microbiota and bile acid metabolism. The results showed that the accumulation of beta-amyloid (Aβ) leads to a significant decrease in Lactobacillus johnsonii and a notable increase in bacteria of the genus Clostridium in the small intestine, which are important microorganisms for producing toxic bile acids. Extracellular vesicles (EVs) involved in bacterial interactions and bacteria-host interactions are currently a focus of research. Treatment with L. johnsonii-derived EVs at concentrations of 10[10] and 10[12]/mL) inhibited the growth of Clostridium scindens and suppressed the production of toxic secondary lithocholic acid (TLA) at non-cytotoxic concentrations (10[8]/mL). Furthermore, the removal of small RNA from L. johnsonii-derived EVs resulted in the loss of their ability to suppress TLA production. These results suggest that the small intestine microbiota may play a more critical role than the colonic microbiota in AD. Deterioration of small intestine microbiota led to the metabolism disruption of certain secondary bile acids, which have been reported to exacerbate AD pathology. The EVs released by L. johnsonii, which is abundant in the small intestine, can suppress toxic TLA and have the potential to be developed into health-promoting probiotics.},
}

Animals
*Probiotics/pharmacology
*Clostridium/metabolism
*Intestine, Small/microbiology/metabolism
*Gastrointestinal Microbiome
*Bile Acids and Salts/metabolism
Mice
*Extracellular Vesicles/metabolism
*Mice, Transgenic
Lactobacillus johnsonii/metabolism
Lithocholic Acid/metabolism
Humans
Alzheimer Disease/metabolism/microbiology

@article {pmid40086910,
year = {2025},
author = {Sankhe, K and Tumati, S and Perin, J and Rivet, L and Vieira, D and Rosenberg, PB and Herrmann, N and Shade, D and Lerner, AJ and Padala, PR and Brawman-Mintzer, O and van Dyck, CH and Porsteinsson, AP and Craft, S and Levey, AI and Mintzer, J and Lanctôt, KL},
title = {Correlation between changes in apathy and cognition in Alzheimer's disease associated apathy: Analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).},
journal = {International psychogeriatrics},
volume = {37},
number = {2},
pages = {100012},
doi = {10.1016/j.inpsyc.2024.100012},
pmid = {40086910},
issn = {1741-203X},
mesh = {Humans ; *Apathy/drug effects ; *Methylphenidate/therapeutic use/pharmacology ; Male ; Female ; Aged ; *Alzheimer Disease/drug therapy/psychology ; *Cognition/drug effects ; *Neuropsychological Tests ; *Central Nervous System Stimulants/therapeutic use ; Aged, 80 and over ; Treatment Outcome ; Double-Blind Method ; },
abstract = {BACKGROUND: Previous trials have shown improvements in both apathy and cognition with methylphenidate (MPH).

OBJECTIVES: To assess whether changes in apathy correlated with changes in cognition in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

PARTICIPANTS: Mild to moderate AD patients with clinically significant apathy randomized to MPH (20 mg/day) or placebo for 6 months.

MEASUREMENTS: Apathy was measured with the Neuropsychiatric Inventory-apathy (NPI-A) domain. Cognition was measured using the Mini-Mental State Exam (MMSE), Hopkins Verbal Learning (immediate [HVLT-I], delayed [HVLT-D] recall), Digit Span (Forward [DF], Backward [DB]), Trail Making (TMT-A, TMT-B), Action Verbal Fluency (AV), Category Fluency (CF), and the Short Boston Naming Test (BNT).

DESIGN: Linear mixed models included cognitive change scores as dependent variables and time, treatment, change in NPI-A and the interaction between treatment and change in NPI-A as independent variables, which were additionally adjusted for baseline NPI-A and cognitive scores, age, sex, level of education and presence of diabetes.

RESULTS: 199 participants (66 % male) were included (98-MPH, 101-placebo). Among all participants, worsening CF was associated with worsening apathy (-0.15 (0.05), p = .003). In addition, change in HVLT-I was associated with the interaction between changes in apathy and treatment (-0.31 (0.07), p = 0.0000158).

CONCLUSION: Changes in apathy are mostly independent of cognitive changes and apathy response to MPH may be independent from cognition. These results are consistent with the view that apathy as a syndrome is related to but distinct from cognition.},
}

Humans
*Apathy/drug effects
*Methylphenidate/therapeutic use/pharmacology
Male
Female
Aged
*Alzheimer Disease/drug therapy/psychology
*Cognition/drug effects
*Neuropsychological Tests
*Central Nervous System Stimulants/therapeutic use
Aged, 80 and over
Treatment Outcome
Double-Blind Method

@article {pmid40086116,
year = {2025},
author = {Lin, G and Liang, W and He, Q and Wang, Y and Yang, X},
title = {Dual single nucleotide polymorphisms typing of apolipoprotein E gene based on double restriction endonuclease with lambda exonuclease and triple helix molecular switch assistance.},
journal = {Biosensors & bioelectronics},
volume = {278},
number = {},
pages = {117365},
doi = {10.1016/j.bios.2025.117365},
pmid = {40086116},
issn = {1873-4235},
abstract = {Single nucleotide polymorphisms (SNPs) are critical determinants of disease susceptibility, pathogenesis, and drug response, underscoring the need for their accurate monitoring in clinical practice. In this study, we propose a novel apolipoprotein E (APOE) genotyping method for the rapid and precise identification of six genotypes (ε2/ε2, ε3/ε3, ε4/ε4, ε2/ε3, ε2/ε4, and ε3/ε4). The method utilizes restriction endonucleases AflIII and HaeII to selectively cleave the rs429358 and rs7412 sites, thereby generating distinct double-stranded DNA fragments. These fragments are subsequently processed by Lambda exonuclease to produce single-stranded DNA, which binds to a triple-helix molecular switch (THMS) and induces its conformational transition into a hairpin structure, resulting in a fluorescence change. The optimized assay exhibits a linear detection range of 5-1000 copies with a minimum detection limit of 2 copies for the rs429358 site, and a range of 10-1000 copies with a minimum detection limit of 6 copies for the rs7412 site. Furthermore, the method was validated using clinical samples from 10 Alzheimer's disease patients, achieving complete concordance with sequencing results, which underlines the high specificity and sensitivity of the method and demonstrates its potential as a valuable tool for the early diagnosis and personalized treatment of Alzheimer's disease.},
}

@article {pmid40084546,
year = {2025},
author = {Magnussen, JH},
title = {Advances in PET Imaging of α7 Nicotinic Receptors: From Radioligand Development to CNS Applications.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {136},
number = {4},
pages = {e70025},
pmid = {40084546},
issn = {1742-7843},
mesh = {*alpha7 Nicotinic Acetylcholine Receptor/metabolism ; *Positron-Emission Tomography/methods ; Humans ; Animals ; *Radiopharmaceuticals/pharmacokinetics ; *Central Nervous System Diseases/drug therapy/diagnostic imaging/metabolism ; Brain/metabolism/diagnostic imaging ; Drug Development/methods ; Ligands ; Blood-Brain Barrier/metabolism ; },
abstract = {Positron emission tomography (PET) has significantly advanced our understanding of the brain by enabling non-invasive imaging and quantification of molecular processes, including receptor binding. In this review, we explore the development and application of PET radioligands targeting the α7 nicotinic acetylcholine receptor (α7 nAChR), a receptor implicated in various central nervous system (CNS) diseases, such as Alzheimer's disease, schizophrenia and cognitive disorders. Despite challenges associated with the low density of α7 nAChRs and difficulties in achieving adequate brain penetration, several promising radioligands have been developed, including [11]C-(R)-MeQAA, [11]C-NS14492 and [18]F-ASEM. These radioligands facilitate the evaluation of the 'three pillars of survival' in drug development: tissue accessibility, target engagement and downstream pharmacology. PET imaging offers critical insights into drug distribution across the blood-brain barrier, receptor occupancy and the pharmacodynamic effects of α7 nAChR-targeted therapies. By reviewing current radioligands and their applications, we highlight the potential of PET imaging to deepen our understanding of α7 nAChR-mediated signalling pathways and its implications for CNS drug discovery. Future innovations in radioligand development, including more selective and brain-penetrant compounds, will be key to fully realizing the potential of PET imaging in α7 nAChR-targeted research and treatment.},
}

*alpha7 Nicotinic Acetylcholine Receptor/metabolism
*Positron-Emission Tomography/methods
Humans
Animals
*Radiopharmaceuticals/pharmacokinetics
*Central Nervous System Diseases/drug therapy/diagnostic imaging/metabolism
Brain/metabolism/diagnostic imaging
Drug Development/methods
Ligands
Blood-Brain Barrier/metabolism

@article {pmid40084342,
year = {2025},
author = {Perez, FP and Walker, B and Morisaki, J and Kanakri, H and Rizkalla, M},
title = {Neurostimulation devices to treat Alzheimer's disease.},
journal = {Exploration of neuroscience},
volume = {4},
number = {},
pages = {},
pmid = {40084342},
issn = {2834-5347},
support = {UL1 TR000006/TR/NCATS NIH HHS/United States ; },
abstract = {The use of neurostimulation devices for the treatment of Alzheimer's disease (AD) is a growing field. In this review, we examine the mechanism of action and therapeutic indications of these neurostimulation devices in the AD process. Rapid advancements in neurostimulation technologies are providing non-pharmacological relief to patients affected by AD pathology. Neurostimulation therapies include electrical stimulation that targets the circuitry-level connection in important brain areas such as the hippocampus to induce therapeutic neuromodulation of dysfunctional neural circuitry and electromagnetic field (EMF) stimulation that targets anti-amyloid molecular pathways to promote the degradation of beta-amyloid (Aβ). These devices target specific or diffuse cortical and subcortical brain areas to modulate neuronal activity at the electrophysiological or molecular pathway level, providing therapeutic effects for AD. This review attempts to determine the most effective and safe neurostimulation device for AD and provides an overview of potential and current clinical indications. Several EMF devices have shown a beneficial or harmful effect in cell cultures and animal models but not in AD human studies. These contradictory results may be related to the stimulation parameters of these devices, such as frequency, penetration depth, power deposition measured by specific absorption rate, time of exposure, type of cell, and tissue dielectric properties. Based on this, determining the optimal stimulation parameters for EMF devices in AD and understanding their mechanism of action is essential to promote their clinical application, our review suggests that repeated EMF stimulation (REMFS) is the most appropriate device for human AD treatments. Before its clinical application, it is necessary to consider the complicated and interconnected genetic and epigenetic effects of REMFS-biological system interaction. This will move forward the urgently needed therapy of EMF in human AD.},
}

@article {pmid40083619,
year = {2025},
author = {Hong, JP and Chen, WF and Nguyen, DH and Xie, Q},
title = {A Proposed Role for Lymphatic Supermicrosurgery in the Management of Alzheimer's Disease: A Primer for Reconstructive Microsurgeons.},
journal = {Archives of plastic surgery},
volume = {52},
number = {2},
pages = {96-103},
pmid = {40083619},
issn = {2234-6163},
abstract = {The relatively recent discovery of a novel lymphatic system within the brain meninges has spurred interest in how waste products generated by neurons and glial cells-including proteins associated with Alzheimer's disease (AD) pathology such as amyloid beta (Aβ) and tau-are disposed of. Evidence is building that suggests disease progression in AD and other cognitive impairments could be explained by dysfunction in the brain's lymphatic system or obstruction of drainage. An interesting implication of this hypothesis is that, by relieving the obstruction of flow, lymphatic reconstruction along the drainage pathway could serve as a potential novel treatment. Should this concept prove true, it could represent a surgical solution to a problem for which only medical solutions have thus far been considered. This study is meant to serve as a primer for reconstructive microsurgeons, introducing the topic and current hypotheses about the potential role of lymphatic drainage in AD. A preview of current research evaluating the feasibility of lymphatic reconstruction as a surgical approach to improving Aβ clearance is provided, with the aim of inspiring others to design robust preclinical and clinical investigations into this intriguing hypothesis.},
}

@article {pmid40083584,
year = {2024},
author = {Pandey, S and Danielsen, MB and Xiang, Y and Zhang, Z and Sharma, G and Jeon, BT and Song, S and Hao, Y and Zhang, G and Christensen, NJ and Sørensen, KK and Harris, P and Pokhrel, P and Cunningham, R and Kim, MH and Leng, Y and Lou, C and Mao, H},
title = {De novo design of a mechano-pharmaceutical screening platform against formation of individual beta-amyloid oligomers.},
journal = {Cell reports. Physical science},
volume = {5},
number = {12},
pages = {},
pmid = {40083584},
issn = {2666-3864},
support = {R01 CA252827/CA/NCI NIH HHS/United States ; },
abstract = {Small molecules that can reduce the neurotoxic beta-amyloid (Aβ) aggregates in the brain provide a potential treatment for Alzheimer disease (AD). Most screening methods for small-molecule hits focus on the overall Aβ aggregations without a specific target, such as the very first association step (i.e., nucleation) en route to the Aβ oligomers. Located in the middle of a full-length Aβ peptide, Aβ19-20 (diphenylalanine or FF) nucleates the neurotoxic Aβ oligomer formation. Here, we innovate a single-molecule screen method in optical tweezers by targeting the nucleation process in Aβ aggregation, namely FF-dimerization. With a 121-compound National Institutes of Health (NIH) library, we identify 12 inhibitors and 8 stimulants that can inhibit/promote Aβ19-20 dimerization significantly. The representative hits are subjected to the thioflavin T and cell toxicity assays to confirm their inhibiting or stimulating activities. By replacing FF with longer Aβ sequences, our single-molecule platform may identify more specific and potent small molecules to fight AD.},
}

@article {pmid40083386,
year = {2025},
author = {Wang, S and Yang, J and Zheng, W and Zhang, S and Zhong, D},
title = {The effect of tanshinones on cognitive impairments in animal models of Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1529327},
pmid = {40083386},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an age-related neurological illness that poses a significant hazard to human health. A fat-soluble compound called tanshinones was isolated from Danshen, a traditional Chinese herb. Recent years have seen reports of clinical trials examining the effects of tanshinones on cognitive impairment among individuals with AD, as well as the publication of pertinent basic research. Tanshinones are not yet commonly utilized in the therapeutic treatment of AD, and the effectiveness of tanshinones as a treatment program for AD is not yet adequately supported by evidence. To assess the impact of tanshinones on cognitive impairment in experimental rodent models of AD, we carried out a systematic review in this work.

METHOD: All relevant studies on the usage of tanshinones in AD model animals published in PubMed, Cochrane Library, Web of Science, EMBASE, Chinese Biomedicine Database, and China National Knowledge Infrastructure before 8 September 2024, were systematically retrieved. To assess the methodological quality, the CAMARADES checklist was used. Meta-analysis was calculated and graphed in the Stata 14.0 software. For each outcome in every study, the standard mean difference (SMD) and the 95% confidence interval (CI) of each effect size were calculated.

RESULTS: Fourteen studies were included in this study. Compared with the AD model group without tanshinones intervention, tanshinones significantly reduced the number of escape latency [SMD = -2.082, 95% CI = (-2.481, -1.683), p < 0.001]. Tanshinones also increased the times of platform crossing [SMD = 1.464, 95% CI = (1.183, 1.744), p < 0.001] and time in target quadrants [SMD = 2.703, 95% CI = (2.132, 3.275), p < 0.001].

CONCLUSION: Tanshinones are thought to have positive effects on cognitive impairment in rodent models of AD, according to the findings of this study. However, the level of quality of the included research may have an impact on the accuracy of positive outcomes. Thus, more high-quality randomized controlled animal studies are required to guide future scientific and clinical research.

identifier CRD42024557980.},
}

@article {pmid40083013,
year = {2025},
author = {Jiang, Y and Guo, Z and Zhou, X and Jiang, N and He, J},
title = {Exploration of working memory retrieval stage for mild cognitive impairment: time-varying causality analysis of electroencephalogram based on dynamic brain networks.},
journal = {Journal of neuroengineering and rehabilitation},
volume = {22},
number = {1},
pages = {58},
pmid = {40083013},
issn = {1743-0003},
support = {ZYYC22001//the 1.3.5 Project for Disciplines of 1435 Excellence Grant from the West China Hospital/ ; Z2024YY002//National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/ ; YJ202373//the Fundamental Research Funds for the Central Universities/ ; XZ202201ZD0001G//the Science and Technology Major Project of Tibetan Autonomous Region of China/ ; },
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnosis ; *Electroencephalography/methods ; *Memory, Short-Term/physiology ; Female ; Male ; Aged ; *Brain/physiopathology ; Nerve Net/physiopathology ; Middle Aged ; Mental Recall/physiology ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is an intermediate stage between the expected cognitive decline of normal aging and Alzheimer's disease (AD). Its management is crucial for it helps intervene and slow the progression of cognitive decline to AD. However, the understanding of the MCI mechanism is not completely clear. As working memory (WM) damage is a common symptom of MCI, this study focused on the core stage of WM, i.e., the memory retrieval stage, to investigate information processing and the causality relationships among brain regions based on electroencephalogram (EEG) signals.

METHOD: 21 MCI and 20 normal cognitive control (NC) participants were recruited. The delayed matching sample paradigm with two different loads was employed to evaluate their WM functions. A time-varying network based on the Adaptive transfer function (ADTF) was constructed on the EEG of the memory retrieval trials.to perform the dynamic brain network analysis.

RESULTS: Our results showed that: (a) Behavioral data analysis: there were significant differences in accuracy and accuracy / reaction time between MCI and NC in tasks with memory load capacity of low load-four and high load-six, especially in tasks with memory load capacity of four. (b) Dynamic brain network analysis: there were significant differences in the dynamic changes of brain network patterns between the two groups during the memory retrieval stage of the WM task. Specifically, in low load WM tasks, the dynamic brain network changes of NC were more regular to accommodate for efficient information processing, with important core nodes showing a transition from bottom to up, while MCI did not display a regular dynamic brain network pattern. Further, the brain functional areas associated with low load WM disorders were mainly located in the left prefrontal lobe (FC1) and right occipital lobe (PO8). Compared with low load WM task, during the high load WM task, the dynamic brain network changes of NC during the memory retrieval stage were regular, and the core nodes exhibited a consistent transition phenomenon from up to bottom to up, which were not observed in MCI.

CONCLUSIONS: Behavioral data in the low load WM task paradigm and abnormal electrophysiological signals in the left prefrontal (FC1) and right occipital lobes (PO8) could be used for MCI diagnosis. This is the first time based on large-scale dynamic network methods to investigate the dynamic network patterns of MCI memory retrieval stages under different load WM tasks, providing a new perspective on the neural mechanisms of WM deficits in MCI patients and providing some reference for the clinical intervention treatment of MCI-WM memory disorders.},
}

Humans
*Cognitive Dysfunction/physiopathology/diagnosis
*Electroencephalography/methods
*Memory, Short-Term/physiology
Female
Male
Aged
*Brain/physiopathology
Nerve Net/physiopathology
Middle Aged
Mental Recall/physiology
Neuropsychological Tests

@article {pmid40082927,
year = {2025},
author = {Meng, X and Li, X and Cao, M and Dong, J and Wang, H and Cao, W and Liu, D and Wang, Y},
title = {Summarizing attributable factors and evaluating risk of bias of Mendelian randomization studies for Alzheimer's dementia and cognitive status: a systematic review and meta-analysis.},
journal = {Systematic reviews},
volume = {14},
number = {1},
pages = {61},
pmid = {40082927},
issn = {2046-4053},
support = {2017YFE0118800-779238//National Key R&D Program of China-European Commission Horizon 2020/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; *Mendelian Randomization Analysis ; *Cognitive Dysfunction ; Risk Factors ; Bias ; Cognition ; },
abstract = {BACKGROUND: No effective treatment is available to delay or reverse the onset and progression of Alzheimer's dementia (AD). Mild cognitive impairment, a clinical state between normal aging and AD, may offer the proper window for AD intervention and treatment. This systematic review aimed to summarize evidence from Mendelian randomization (MR) studies exploring factors attributable to AD and related cognitive status and to assess its credibility.

METHODS: We searched PubMed, Embase, MEDLINE, and the Cochrane Library to identify MR studies investigating the associations between any factor and AD and related cognitive status. The risk of bias in MR studies was evaluated using nine signaling questions tailored to identify potential biases based on the STROBE-MR guidelines.

RESULTS: A total of 125 eligible publications were examined, including 106 AD-related MR studies reporting 674 records and 28 cognition-related MR studies reporting 141 records. We identified 185 unique causal risk factors for AD and 49 for cognitive status. More than half of the MR studies reporting AD or cognitive status outcomes exhibited poor methodological quality, with a high risk of bias observed in 59% of the AD-related studies and 64% of the cognitive-related studies.

CONCLUSIONS: This systematic review summarized modifiable factors and omics signatures, providing a database of MR studies on AD and related cognitive status. The evaluation of bias risk in MR studies serves to raise awareness and improve overall quality. A critical appraisal checklist for assessing the risk of bias may pave the way for the development of a standardized tool.

The review protocol was registered with the Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023213990.},
}

Humans
*Alzheimer Disease/genetics
*Mendelian Randomization Analysis
*Cognitive Dysfunction
Risk Factors
Bias
Cognition

@article {pmid40081955,
year = {2025},
author = {Tunali, I and Wang, J and Arora, AK and Kim, MJ and Shcherbinin, S and Pontecorvo, M and Iaccarino, L},
title = {Development and Validation of a [18]F-Flortaucipir PET Visual Stratification Method.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.124.268700},
pmid = {40081955},
issn = {1535-5667},
abstract = {Tau PET quantitation methods have been used in research settings and clinical trials to measure tau burden for diagnostic, staging, and prognostic purposes. However, these methods require specialized software, skilled analysts, and advanced image processing. We developed a novel [18]F-flortaucipir PET (FTP, or Tauvid) visual read method enabling stratification of patients with Alzheimer disease (AD) according to the tau level without the need for quantitation. An independent reader study (I7E-AV-A26) was conducted to test this method against a quantitation-based high-tau standard of truth. Methods: A total of 140 baseline or screening FTP scans were randomly selected from the TRAILBLAZER-ALZ 2 phase 3 trial (NCT04437511). Five qualified imaging physicians were trained for the FTP visual stratification method, using previously identified thresholds and cortical regions of interest thought to optimally stratify high-tau and non-high-tau scans. Positive and negative percent agreement (PPA and NPA, respectively) between visual stratifications and quantitation-based high tau (AD-signature SUV ratio > 1.46) were calculated. Predefined success criteria were met if the lower bounds of a 2-sided 95% CI for PPA and NPA were 50% or greater for at least 3 of the 5 readers. Inter- and intrareader reliability were assessed using Fleiss κ (n = 140) and Cohen κ (n = 20 test-retest scans) metrics. Results: The median PPA and NPA were 83.4% and 88.9%, respectively, with lower bounds of 2-sided 95% CIs being 50% or greater for all readers. The Fleiss κ-point estimate was 0.8882 (95% CI, 0.8356-0.9409) and the Cohen κ-point estimate was 0.9599 (95% CI, 0.9049-1.000) for all readers, indicating almost perfect inter- and intrareader agreement. Study I7E-AV-A26 successfully validated the feasibility of the FTP visual stratification method, possibly supporting AD staging and prognosis with high inter- and intrareader agreements, confirming the reliability of the method. Conclusion: Future investigations may include expanding the validation dataset, including real-world clinical data from diverse populations, using autopsy confirmation, exploring alternative regions and thresholds for other tau PET stratifications, and assessing differences in treatment response among visually stratified participants enrolled in disease-modifying therapy trials.},
}

@article {pmid40081796,
year = {2025},
author = {Chen, G and Zhang, K and Sun, M and Xie, N and Wu, L and Zhang, G and Guo, B and Huang, C and Man Hoi, MP and Zhang, G and Shi, C and Sun, Y and Zhang, Z and Wang, Y},
title = {Multi-functional Memantine Nitrate Attenuated Cognitive Impairment in Models of Vascular Dementia and Alzheimer's Disease through Neuroprotection and Increased Cerebral Blood Flow.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110410},
doi = {10.1016/j.neuropharm.2025.110410},
pmid = {40081796},
issn = {1873-7064},
abstract = {Alzheimer's disease (AD) and vascular dementia (VaD) are two prevalent forms of dementia. VaD is linked to cerebrovascular lesions, such as those from white matter ischemia and chronic cerebral hypoperfusion, which can also occur in AD. Nitric oxide (NO) regulates cerebral blood flow (CBF) in the central nervous system. Memantine is an NMDA receptor antagonist approved for AD treatment. This study investigated the efficacy and molecular mechanism of MN-08, a novel memantine nitrate, in one VaD model (2VO) and two AD models (APP/PS1 mice and Aβ1-42-induced mice). MN-08 increased CBF, ameliorated cognitive and memory functions in VaD and AD, and was more effective than memantine. MN-08 increased the survival rate of CA1 neurons and mitigated white matter lesions and axonal damage. Moreover, MN-08 protected neurons from OGD-induced loss and promoted axonal outgrowth in the hippocampus by upregulating phosphorylated Akt (p-Akt), glycogen synthase kinase-3β (p-GSK3β), and high-molecular-weight neurofilaments (p-NFH). The beneficial effects of MN-08 were attenuated by carboxy-PTIO, a potent NO scavenger, suggesting that MN-08-derived NO may alleviate cognitive impairment from cerebral hypoperfusion. Taken together, our studies demonstrate that MN-08 is a promising therapeutic agent for the treatment of dementia including VaD and AD.},
}

@article {pmid40081504,
year = {2025},
author = {Guo, Y and Liu, T and Chen, H and Zhou, L and Huang, W and Zhang, K and Wang, X and Wang, Y and Zhou, JH and Chen, F and , },
title = {Decreased brain interstitial fluid dynamics is associated with risk of Alzheimer's disease-related cognitive decline.},
journal = {Brain research bulletin},
volume = {224},
number = {},
pages = {111295},
doi = {10.1016/j.brainresbull.2025.111295},
pmid = {40081504},
issn = {1873-2747},
abstract = {BACKGROUND: Diffusion-tensor image analysis along the perivascular space (ALPS) index that has the potential to reflect brain interstitial fluid (ISF) dynamics may predict the development of Alzheimer's Disease (AD). We aimed to study whether brain ISF dynamics indicated by the ALPS index relate to AD dementia diagnosis and AD-related changes.

METHODS: This study included a discovery cohort (n = 180) and a validation cohort (n = 127), which were composed of cognitively normal, subjective memory concern, mild cognitive impairment, and AD dementia subjects. All participants underwent brain magnetic resonance imaging examination and neuropsychological evaluation. The diffusivities and diffusion-tensor image analysis along the perivascular space (ALPS) were calculated. The support vector machine (SVM) model for AD dementia diagnosis was built in the discovery cohort and validated in the validation cohort. Linear mixed-effects models were used to evaluate the association between the ALPS and cognitive decline. Cox regression models were used to evaluate the association between the ALPS and the risk of AD dementia.

RESULTS: There was a lower median ALPS index in the AD dementia group compared to other groups (all P < 0.05) for both cohorts. The SVM model for AD dementia diagnosis produced an AUC of 0.802 in the discovery cohort (P < 0.001) and 0.783 in the external validation cohort (P < 0.001). Higher ALPS levels were associated with less cognitive decline (P < 0.001). Moreover, lower baseline ALPS had a greater risk of converting to AD dementia (P = 0.014).

CONCLUSIONS: The SVM model based on diffusivities and ALPS was effective for AD dementia diagnosis, and higher ALPS levels are associated with a lower risk of AD-related changes. These findings suggest that ALPS may provide a useful AD progression or treatment biomarker.},
}

@article {pmid40081261,
year = {2025},
author = {Yang, R and Meng, X and Zhao, W and Xu, SQ and Wang, SY and Li, MM and Guan, W and Chen, QS and Zhang, LL and Kuang, HX and Li, H and Yang, BY and Liu, Y},
title = {Phenylpropanoids of Eleutherococcus senticosus (Rupr. & maxim.) maxim. Alleviate oxidative stress in Alzheimer's disease in vitro and in vivo models by regulating Mst1 and affecting the Nrf2/Sirt3 pathway.},
journal = {Bioorganic chemistry},
volume = {159},
number = {},
pages = {108347},
doi = {10.1016/j.bioorg.2025.108347},
pmid = {40081261},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder, and oxidative stress plays a significant role in its progression. Owing to its nourishing effects, Eleutherococcus senticosus (Rupr. & maxim.) maxim. (ES) has gained widespread popularity globally as a functional food and long-term consumption has been shown to enhance memory. The phenylpropanoid components extracted from Eleutherococcus senticosus (Rupr. & maxim.) maxim. (ESP) exhibit a diverse array of bioactivities and are commonly employed in the treatment of central nervous system (CNS) disorders. Nonetheless, the exact mechanisms by which ESP alleviates oxidative stress in AD models require further investigation. Therefore, this study utilized SAMP8 mice as models for AD and employed L-glutamate (L-Glu)-induced HT22 cells to establish an in vitro AD model. The effects of ESP on cognitive function were evaluated using the Morris water maze (MWM) test. Additionally, various techniques such as pathology, immunofluorescence staining (IF), ROS staining, cellular thermal shift assay (CETSA), Mst1 inhibitor analysis, and western blotting (WB) were conducted to further investigate the pharmacological efficacy and potential molecular mechanisms of ESP. In vivo, ESP was found to improve cognitive function in SAMP8 mice and alleviate AD-like pathological features. In vitro, ESP reduced intracellular ROS levels. Mechanistically, CETSA analysis confirmed the binding affinity between ESP and Mst1, demonstrated that ESP modulated the Mst1 signaling pathway to mitigate oxidative stress and decrease ROS levels. These findings suggested that ESP holded significant potential for developing therapeutic strategies for AD.},
}

@article {pmid40081008,
year = {2025},
author = {Lin, M and Tang, K and Zheng, W and Zheng, S and Hu, K},
title = {Curcumin delivery system based on a chitosan-liposome encapsulated zeolitic imidazolate framework-8: A potential treatment antioxidant and antibacterial treatment after phacoemulsification.},
journal = {Biomedical materials (Bristol, England)},
volume = {},
number = {},
pages = {},
doi = {10.1088/1748-605X/adc05c},
pmid = {40081008},
issn = {1748-605X},
abstract = {Curcumin is a natural polyphenol extracted from plants that interacts with various molecular targets and exhibits antioxidant, antibacterial, anticancer, and anti-aging properties. Due to its various pharmacological activities and high safety margin, curcumin has been used in the prevention and treatment of various diseases, including Alzheimer's, heart, and rheumatic immune diseases. To develop curcumin eye drops that can be used as antioxidant and antibacterial agents after phacoemulsification, we designed a nano-based drug delivery system to improve curcumin bioavailability and duration of action. We successfully prepared a zeolitic imidazolate framework-8 (ZIF-8) coated with chitosan-liposome for curcumin delivery (Cur@ZIF-8/CS-Lip). This system enables sustained curcumin release for over 20 h in vitro and exhibits excellent biosafety, antioxidant, and antibacterial activities. Therefore, we proposed that Cur@ZIF-8/CS-Lip may reduce the incidence of oxidative stress and infections following cataract surgery. .},
}

@article {pmid40080205,
year = {2025},
author = {Nadais, A and Martins, I and Henriques, AG and Trigo, D and da Cruz E Silva, OAB},
title = {Comparing In vitro Protein Aggregation Modelling Using Strategies Relevant to Neuropathologies.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {24},
pmid = {40080205},
issn = {1573-6830},
support = {SFRH/BD/121289/2016//Fundação para a Ciência e a Tecnologia/ ; EXPL/BTM-SAL/0902/2021//Fundação para a Ciência e a Tecnologia/ ; PTDC/DTPPIC/5587/2014//Fundação para a Ciência e a Tecnologia/ ; CI21-00276//'la Caixa' Foundation/ ; CENTRO-01-0145-FEDER-000003//CCDRC/ ; CENTRO-01-0145-FEDER-000003//CCDRC/ ; POCI-01-0145-FEDER-016904//COMPETE 2020/ ; },
mesh = {Humans ; Cell Line, Tumor ; *Amyloid beta-Peptides/metabolism ; *Rotenone/pharmacology ; Protein Aggregates/drug effects ; Peptide Fragments/metabolism ; Protein Aggregation, Pathological/metabolism/pathology ; Models, Biological ; Leupeptins/pharmacology ; tau Proteins/metabolism ; Oligomycins/pharmacology ; },
abstract = {Protein aggregation is remarkably associated with several neuropathologies, including Alzheimer´s (AD) and Parkinson´s disease (PD). The first is characterized by hyperphosphorylated tau protein and Aβ peptide deposition, thus forming intracellular neurofibrillary tangles and extracellular senile plaques, respectively; while, in PD, α-synuclein aggregates and deposits as Lewy bodies. Considerable research has focused on developing protein aggregation models to be explored as research tools. In the present work, four in vitro models for studying protein aggregation were studied and compared, namely treatment with: the toxic Aβ1-42 peptide, the isoflavone rotenone, the ATP synthase inhibitor oligomycin, and the proteosome inhibitor MG-132. All treatments result in aggregation-relevant events in the human neural SH-SY5Y cell line, but significant model-dependent differences were observed. In terms of promoting aggregate formation, Aβ and MG-132 provoked the greatest effect, but only MG-132 was associated with an increase in HSP-70 chaperone expression. In fact, the type of aggregates formed appear to be dependent on the treatment employed, and supports the hypothesis that Aβ exposure is a relevant AD model, and rotenone is a valid model for PD. Furthermore, the results revealed that protein phosphorylation is relevant to aggregate formation and as expected, tau co-localized to the deposits formed in the Aβ peptide aggregate induction cell model. In summary, different molecular processes, from overall and specific protein aggregation to proteostatic modulation, can be induced by using distinct aggregation modelling strategies, and these can be used to study different protein-aggregation-related processes associated with distinct neuropathologies.},
}

Humans
Cell Line, Tumor
*Amyloid beta-Peptides/metabolism
*Rotenone/pharmacology
Protein Aggregates/drug effects
Peptide Fragments/metabolism
Protein Aggregation, Pathological/metabolism/pathology
Models, Biological
Leupeptins/pharmacology
tau Proteins/metabolism
Oligomycins/pharmacology

@article {pmid40079275,
year = {2025},
author = {Pang, S and Li, Z and Liu, A and Luo, ZH and Yin, H and Fan, S and Shi, J and Liu, N and Pan, S and Yang, YJ and Zhang, GJ and Chen, J},
title = {A Novel Oxo-Palmatine Derivative 2q as Potent Reversal Agents Against Alzheimer's Disease.},
journal = {Drug development research},
volume = {86},
number = {2},
pages = {e70073},
doi = {10.1002/ddr.70073},
pmid = {40079275},
issn = {1098-2299},
support = {//This study was supported by the Beijing Natural Science Foundation (grant no. 7244343), National Natural Science Foundation of China (grant no. 82401383, 82471472), Joint Basic-Clinical Laboratory of Pediatric Epilepsy and Cognitive Developmental (grant no. 3-1-013-03), and the Drug Innovation Major Project (2018ZX09711-001-005)./ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Berberine Alkaloids/pharmacology/therapeutic use/chemistry ; Mice ; Humans ; Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Male ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; Phosphorylation/drug effects ; },
abstract = {Palmatine (PAL), as an active ingredient in traditional Chinese medicine, had been demonstrated efficacy in ameliorating the manifestations of AD. Our research group has previously designed and synthesized the novel oxo-PAL derivative 2q and found that it has exhibited notable neuroprotective properties. However, compound 2q therapeutic impact on AD remains uncertain. In the current investigation, our findings demonstrated that compound 2q displayed significant anti-AβOs activity in vitro by using xCELLigence analysis, and showed a high likelihood of crossing the blood-brain barrier. Furthermore, administration of compound 2q yielded a notable amelioration in Aβ accumulation and hyperphosphorylation of Tau in 3×Tg mice. Additionally, it was observed that compound 2q potentially enhanced the pathological characteristics of AD by targeting Potassium/Sodium Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 (HCN2). In conclusion, compound 2q emerged as a promising candidate for AD treatment, as it effectively restored AD-associated pathological impairments. Furthermore, it has been identified as a potential target of HCN2, thereby offering novel avenues for the development of treatments for AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Berberine Alkaloids/pharmacology/therapeutic use/chemistry
Mice
Humans
Neuroprotective Agents/pharmacology/therapeutic use/chemistry
Mice, Transgenic
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Male
Blood-Brain Barrier/metabolism/drug effects
Disease Models, Animal
Phosphorylation/drug effects

@article {pmid40077790,
year = {2025},
author = {Gualtieri, P and Frank, G and Cianci, R and Ciancarella, L and Romano, L and Ortoman, M and Bigioni, G and Nicoletti, F and Falco, MI and La Placa, G and Di Renzo, L},
title = {Exploring the Efficacy and Safety of Nutritional Supplements in Alzheimer's Disease.},
journal = {Nutrients},
volume = {17},
number = {5},
pages = {},
pmid = {40077790},
issn = {2072-6643},
support = {PNRR-MAD-2022-12376383, CIMA//Ministero della Salute/ ; },
mesh = {*Alzheimer Disease ; Humans ; *Dietary Supplements ; Fatty Acids, Omega-3/administration & dosage ; Curcumin/therapeutic use/administration & dosage ; Probiotics/therapeutic use/administration & dosage ; Vitamin E/administration & dosage ; Resveratrol ; Melatonin/administration & dosage/therapeutic use ; Treatment Outcome ; },
abstract = {Background: Alzheimer's disease (AD) represents one of the major challenges of modern medicine, with a growing impact on public health and healthcare systems. In recent years, dietary supplements use has been the subject of increasing interest as a complementary strategy for the prevention and treatment of the disease. Materials and Methods: A Review of reviews was conducted following PRISMA guidelines and REAPPRAISED checklist to evaluate the efficacy and safety of supplement use in AD. The search, performed across major scientific databases, identified 54 relevant articles, including 53 reviews and one mini-review, after applying specific inclusion criteria and removing duplicates. Results: The growing body of evidence suggests that some supplements may help reduce cognitive decline, inflammation, and target mechanisms behind AD. However, many of these supplements are still under investigation, with mixed results highlighting the need for high-quality research. A key challenge is the lack of data on optimal dosages, administration duration, and long-term safety, which limits clinical guidelines. Some studies have reported positive effects from specific regimens, such as curcumin (800 mg/day), omega-3 fatty acids (2 g/day), and resveratrol (600 mg/day). Other supplements, like phosphatidylserine (300 mg/day), multinutrient formulations, probiotics, vitamin E (2000 IU/day), and melatonin (3-10 mg/day), also show benefits, though study variability makes conclusions uncertain. Conclusions: While certain supplements show potential in mitigating cognitive decline in AD, inconsistent findings and gaps in dosage and safety data highlight the need for rigorous, large-scale trials. Future research should focus on personalized, multimodal strategies integrating targeted supplementation, dietary patterns, and microbiota-gut-brain interactions for enhanced neuroprotection.},
}

*Alzheimer Disease
Humans
*Dietary Supplements
Fatty Acids, Omega-3/administration & dosage
Curcumin/therapeutic use/administration & dosage
Probiotics/therapeutic use/administration & dosage
Vitamin E/administration & dosage
Resveratrol
Melatonin/administration & dosage/therapeutic use
Treatment Outcome

@article {pmid40076984,
year = {2025},
author = {Li, J and Wang, M and Wang, Y and Peng, X and Lv, G and Zheng, T and Peng, Y and Li, J},
title = {Revealing Lingonberry's Neuroprotective Potential in Alzheimer's Disease Through Network Pharmacology and Molecular Docking.},
journal = {International journal of molecular sciences},
volume = {26},
number = {5},
pages = {},
pmid = {40076984},
issn = {1422-0067},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Molecular Docking Simulation ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Humans ; *Vaccinium vitis-idaea/chemistry ; Network Pharmacology ; Molecular Dynamics Simulation ; Coumaric Acids/chemistry/pharmacology/therapeutic use ; Monoamine Oxidase/metabolism/chemistry ; Plant Extracts/chemistry/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder with limited treatment options. Lingonberry (Vaccinium vitis-idaea L.) has demonstrated neuroprotective and anti-inflammatory properties, yet the underlying mechanisms remain unclear. This study employed network pharmacology, molecular docking, and molecular dynamics simulations to explore the therapeutic potential in Alzheimer's disease. Pathway analysis identified monoamine oxidase B as a key target involved in serotonergic synapse dysfunction related to Alzheimer's disease. Molecular docking revealed that ferulic acid, a major bioactive compound in lingonberry, exhibits strong binding affinity to monoamine oxidase B. Further molecular dynamics simulations confirmed the stability of this interaction, highlighting the potential inhibitory effect of ferulic acid on monoamine oxidase B. These findings provide novel insights into the neuroprotective mechanisms of lingonberry and suggest its potential as a natural therapeutic intervention for Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy/metabolism
*Molecular Docking Simulation
*Neuroprotective Agents/pharmacology/therapeutic use/chemistry
Humans
*Vaccinium vitis-idaea/chemistry
Network Pharmacology
Molecular Dynamics Simulation
Coumaric Acids/chemistry/pharmacology/therapeutic use
Monoamine Oxidase/metabolism/chemistry
Plant Extracts/chemistry/pharmacology/therapeutic use

@article {pmid40076831,
year = {2025},
author = {Wang, S and Xiao, L},
title = {Progress in AAV-Mediated In Vivo Gene Therapy and Its Applications in Central Nervous System Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {5},
pages = {},
pmid = {40076831},
issn = {1422-0067},
support = {2021ZD0201703//STI 2030-Major Project/ ; 32170957//National Natural Science Foundation of China/ ; 31970913//National Natural Science Foundation of China/ ; 2021A1515012156//Guangdong Basic and Applied Basic Research Foundation/ ; 2019B030335001//Key-Area Research and Development Program of Guang-dong Province/ ; },
mesh = {*Dependovirus/genetics ; Humans ; *Genetic Therapy/methods ; *Genetic Vectors/genetics ; Animals ; *Central Nervous System Diseases/therapy/genetics ; Blood-Brain Barrier/metabolism ; Gene Transfer Techniques ; },
abstract = {As the blood-brain barrier (BBB) prevents molecules from accessing the central nervous system (CNS), the traditional systemic delivery of chemical drugs limits the development of neurological drugs. However, in recent years, innovative therapeutic strategies have tried to bypass the restriction of traditional drug delivery methods. In vivo gene therapy refers to emerging biopharma vectors that carry the specific genes and target and infect specific tissues; these infected cells and tissues then undergo fundamental changes at the genetic level and produce therapeutic proteins or substances, thus providing therapeutic benefits. Clinical and preclinical trials mainly utilize adeno-associated viruses (AAVs), lentiviruses (LVs), and other viruses as gene vectors for disease investigation. Although LVs have a higher gene-carrying capacity, the vector of choice for many neurological diseases is the AAV vector due to its safety and long-term transgene expression in neurons. Here, we review the basic biology of AAVs and summarize some key issues in recombinant AAV (rAAV) engineering in gene therapy research; then, we summarize recent clinical trials using rAAV treatment for neurological diseases and provide translational perspectives and future challenges on target selection.},
}

*Dependovirus/genetics
Humans
*Genetic Therapy/methods
*Genetic Vectors/genetics
Animals
*Central Nervous System Diseases/therapy/genetics
Blood-Brain Barrier/metabolism
Gene Transfer Techniques

@article {pmid40076742,
year = {2025},
author = {Wen, S and Han, Y and Li, Y and Zhan, D},
title = {Therapeutic Mechanisms of Medicine Food Homology Plants in Alzheimer's Disease: Insights from Network Pharmacology, Machine Learning, and Molecular Docking.},
journal = {International journal of molecular sciences},
volume = {26},
number = {5},
pages = {},
pmid = {40076742},
issn = {1422-0067},
support = {20210202109NC//Key R&D Project of the Jilin Province Science and Technology Development Plan/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Molecular Docking Simulation ; Humans ; *Machine Learning ; *Network Pharmacology ; Plants, Medicinal/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function. Currently, there are no effective treatments for this condition. Medicine food homology plants have gained increasing attention as potential natural treatments for AD because of their nutritional value and therapeutic benefits. In this work, we aimed to provide a deeper understanding of how medicine food homology plants may help alleviate or potentially treat AD by identifying key targets, pathways, and small molecule compounds from 10 medicine food homology plants that play an important role in this process. Using network pharmacology, we identified 623 common targets between AD and the compounds from the selected 10 plants, including crucial proteins such as STAT3, IL6, TNF, and IL1B. Additionally, the small molecules from the selected plants were grouped into four clusters using hierarchical clustering. The ConPlex algorithm was then applied to predict the binding capabilities of these small molecules to the key protein targets. Cluster 3 showed superior predicted binding capabilities to STAT3, TNF, and IL1B, which was further validated by molecular docking. Scaffold analysis of small molecules in Cluster 3 revealed that those with a steroid-like core-comprising three fused six-membered rings and one five-membered ring with a carbon-carbon double bond-exhibited better predicted binding affinities and were potential triple-target inhibitors. Among them, MOL005439, MOL000953, and MOL005438 were identified as the top-performing compounds. This study highlights the potential of medicine food homology plants as a source of active compounds that could be developed into new drugs for AD treatment. However, further pharmacokinetic studies are essential to assess their efficacy and minimize side effects.},
}

*Alzheimer Disease/drug therapy/metabolism
*Molecular Docking Simulation
Humans
*Machine Learning
*Network Pharmacology
Plants, Medicinal/chemistry

@article {pmid40076682,
year = {2025},
author = {Guo, H and Yang, R and Cheng, W and Li, Q and Du, M},
title = {An Update of Salivary Biomarkers for the Diagnosis of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {5},
pages = {},
pmid = {40076682},
issn = {1422-0067},
support = {82301091//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/diagnosis/metabolism/cerebrospinal fluid ; Humans ; *Biomarkers/cerebrospinal fluid ; *Saliva/metabolism ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid/analysis ; tau Proteins/metabolism/cerebrospinal fluid ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognition and behavior impairments. Diagnosing AD early is important for clinicians to slow down AD progression and preserve brain function. Biomarkers such as tau protein and amyloid-β peptide (Aβ) are used to aid diagnosis as clinical diagnosis often lags. Additionally, biomarkers can be used to monitor AD status and evaluate AD treatment. Clinicians detect these AD biomarkers in the brain using positron emission tomography/computed tomography or in the cerebrospinal fluid using a lumbar puncture. However, these methods are expensive and invasive. In contrast, saliva collection is simple, inexpensive, non-invasive, stress-free, and repeatable. Moreover, damage to the brain parenchyma can impact the oral cavity and some pathogenic molecules could travel back and forth from the brain to the mouth. This has prompted researchers to explore biomarkers in the saliva. Therefore, this study provides an overview of the main finding of salivary biomarkers for AD diagnosis. Based on these available studies, Aβ, tau, cholinesterase enzyme activity, lactoferrin, melatonin, cortisol, proteomics, metabolomics, exosomes, and the microbiome were changed in AD patients' saliva when compared to controls. However, well-designed studies are essential to confirm the reliability and validity of these biomarkers in diagnosing and monitoring AD.},
}

*Alzheimer Disease/diagnosis/metabolism/cerebrospinal fluid
Humans
*Biomarkers/cerebrospinal fluid
*Saliva/metabolism
Amyloid beta-Peptides/metabolism/cerebrospinal fluid/analysis
tau Proteins/metabolism/cerebrospinal fluid

@article {pmid40076562,
year = {2025},
author = {Pokrzyk, J and Kulczyńska-Przybik, A and Guzik-Makaruk, E and Winkel, I and Mroczko, B},
title = {Clinical Importance of Amyloid Beta Implication in the Detection and Treatment of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {5},
pages = {},
pmid = {40076562},
issn = {1422-0067},
support = {SUB.B24.559.01.S//Medical Univerity of Białystok/ ; },
mesh = {*Alzheimer Disease/diagnosis/metabolism/therapy ; Humans ; *Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism/diagnostic imaging/pathology ; Positron-Emission Tomography/methods ; Biomarkers ; Clinical Relevance ; },
abstract = {The role of amyloid beta peptide (Aβ) in memory regulation has been a subject of substantial interest and debate in neuroscience, because of both physiological and clinical issues. Understanding the dual nature of Aβ in memory regulation is crucial for developing effective treatments for Alzheimer's disease (AD). Moreover, accurate detection and quantification methods of Aβ isoforms have been tested for diagnostic purposes and therapeutic interventions. This review provides insight into the current knowledge about the methods of amyloid beta detection in vivo and in vitro by fluid tests and brain imaging methods (PET), which allow for preclinical recognition of the disease. Currently, the priority in the development of new therapies for Alzheimer's disease has been given to potential changes in the progression of the disease. In light of increasing amounts of data, this review was focused on the diagnostic and therapeutic employment of amyloid beta in Alzheimer's disease.},
}

*Alzheimer Disease/diagnosis/metabolism/therapy
Humans
*Amyloid beta-Peptides/metabolism
Animals
Brain/metabolism/diagnostic imaging/pathology
Positron-Emission Tomography/methods
Biomarkers
Clinical Relevance